Pubmed abstracts for Protein-Protein Interaction search result :

Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.5545483
We analysed p 53 and p14arf in relation with five other genetic loci encoding the most frequently mutated genes in human gliomas : cdkn2a , mdm 2 , egfr , pten and the chromosomal regions 10q23 . 3 and 10q25 26 . 0.5545483^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.52833708
A physical association between p14ARF and MDM 2 blocks MDM 2 induced p 53 degradation , resulting in increased levels of p 53 , which in turn leads to cell cycle arrest . 0.52833708^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :1.0742308
Both mutations occur within the N terminal region of p14ARF , documented as important for nucleolar localization and interaction with Mdm 2 . 1.0742308^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.74282683
This is one of the first reports that describe the interaction of p14ARF with a protein besides HDM 2 , which may define a p 53 independent tumor suppressor activity for p14ARF . . 0.74282683^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.73955125
Here we relate physical interactions between p14ARF and MDM 2 , as determined using synthetic peptides and systematic deletions of p14ARF , with consequential effects on p 53 stabilization and transcriptional activity . 0.73955125^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.97215522
ARF prevents G 1 cyclin dependent kinase activation by interacting with MDM 2 and activating p 53 in mouse fibroblasts . p19ARF encoded by the INK4a tumor suppressor gene locus functions upstream of p 53 to induce cell cycle arrest . p19ARF can interact with MDM 2 and p 53 in cells ectopically overexpressing these three components , but the biochemical cascades from p19ARF to cell cycle arrest has not been fully elucidated . 0.97215522^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.82046011
We show here that ARF binds to MDM 2 and promotes the rapid degradation of MDM 2 . 0.82046011^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.56108616
ARF binds directly to Mdm 2 to prevent down regulation of p 53 and thereby promotes p 53 dependent transcription and cell cycle arrest . 0.56108616^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.66318218
ARF forms nuclear bodies with MDM 2 and p 53 and blocks p 53 and MDM 2 nuclear export . 0.66318218^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.88085975
ARF binds directly to MDM 2 , and prevents MDM 2 from targeting p 53 for degradation [ 6 ] [ 7 ] [ 8 ] [ 9 ] by inhibiting the E 3 ligase activity of MDM 2 [ 2 ] and preventing nuclear export of MDM 2 and p 53 [ 10 ] [ 11 ] . 0.88085975^^^ Interaction between ARF and MDM 2 results in the localization of both proteins to the nucleolus [ 12 ] [ 13 ] [ 14 ] through nucleolar localization signals ( NoLS ) in ARF and MDM 2 [ 11 ] [ 12 ] [ 13 ] [ 14 ] . 0.69462982^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :1.1751491
Finally , we demonstrate that while ARF can interact with MDM 2 and inhibit the regulation of p 53 by MDM 2 , no interaction was found between ARF and MDMX . 1.1751491^^^ MDM 2 and MDMX can interact differently with ARF and members of the p 53 family . 0.82902333^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :1.075359
Using alternative reading frames , the human ARF INK4a locus encodes two unrelated proteins that both function in tumor suppression . p 16 ( INK4a ) maintains the retinoblastoma protein in its growth suppressive state through inhibition of cyclin D dependent kinase activity , whereas ARF binds with MDM 2 and stabilizes p 53 . 1.075359^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.83232755
These data are consistent with a model in which ARF interacts with MDM 2 in the nucleoplasm but is consequently subject to proteasomal degradation . 0.83232755^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Like p16INK4a , p14ARF is involved in cell cycle regulation , blocking cells at the G 1 restriction point through the activity of MDM 2 and p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Recent evidence has shown that P14ARF binds to MDM 2 leading to an increased availability of wild type TP 53 protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p14ARF gene product can complex with and sequester the MDM 2 protein within the nucleus , thus modulating the activity of the p 53 protein . ^^^ Loss of p16INK4a expression would disrupt the retinoblastoma ( Rb ) / p16INK4a / cyclin D dependent kinase ( CDK 4 ) pathway , whereas loss of p14ARF expression would inactivate both the Rb and p53 / MDM2 / p14ARF pathways through MDM 2 , which can complex with either Rb or p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Recent investigations suggest that p14ARF is induced in response to abnormal cell cycle entry and results in p 53 accumulation by inhibiting MDM 2 mediated transactivational silencing and degradation of p 53 . ^^^ Seventy six percent of GBs ( 103 of 136 ) , 72 % of AAs ( 28 of 39 ) , and 67 % of As ( 10 of 15 ) had deregulated p 53 pathway either by mutation of TP 53 , amplification of MDM 2 , or homozygous deletion / mutation of p14ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We have compared the association of DNA bound and overall pools of p 53 with murine double minute 2 ( Mdm 2 ) , c Jun NH 2 terminal kinase ( JNK ) , p300 / CBP , and p14ARF during cell cycle progression . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p14ARF product , a tumor suppresser gene located on the INK4a / ARF locus , acts as one of the major factors affecting p 53 mdm2 interactions via its binding to mdm 2 and the stimulation of mdm 2 degradation . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
An N terminal p14ARF peptide blocks Mdm 2 dependent ubiquitination in vitro and can activate p 53 in vivo . ^^^ The p14ARF protein is also a potent tumour suppressor that acts by binding to Mdm 2 and blocking Mdm 2 dependent p 53 degradation and transcriptional silencing . ^^^ We have screened a series of overlapping synthetic peptides derived from the p14ARF protein sequence and found that a peptide corresponding to the first 20 amino acids of ARF ( Peptide 3 ) could bind human Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The amino terminal nucleolar targeting domain of p14ARF is also important for ARF hdm 2 binding and cell cycle inhibition . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Analysis of the p16INK4 , p14ARF , p 15 , TP 53 , and MDM 2 genes and their prognostic implications in osteosarcoma and Ewing sarcoma . ^^^ We examined alterations of the p16INK4 , p14ARF , p 15 , TP 53 , and MDM 2 genes in 30 osteosarcomas and 24 Ewing sarcomas . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p 53 dependent pathway involves the induction by E2F 1 of the human tumour suppressor protein p14ARF , which neutralizes HDM 2 ( human homologue of MDM 2 ) and thereby stabilizes the p 53 protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Cell growth regulators include proteins of the p 53 pathway encoded by the genes CDKN2A ( p 16 , p14arf ) , MDM 2 , TP 53 , and CDKN1A ( p 21 ) as well as proteins encoded by genes like RB 1 , E2F , and MYCL . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In 10 irradiated human cells , HDM 2 protein was rapidly phosphorylated in serine / threonine residues in a p 53 , p14ARF and p 73 independent manner . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Aberrant expression of pRb , p 16 , p14ARF , MDM 2 , p 21 and p 53 in squamous cell carcinomas of lung . ^^^ MDM 2 and p14ARF expressions were each observed in about half of the cases of SCC and were not significantly associated with strong p 53 immunoreactivity . ^^^ Statistical analysis revealed that p14ARF expression was significantly correlated with both p 16 and MDM 2 expression . ^^^ These results suggest that disruption of the RB and p 53 pathways is a frequent event in SCC , and that abnormal expression of p 16 and p 53 plays a more critical role than that of pRB , p14ARF and MDM 2 in the development of SCC of the lung . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Because it is known that p14ARF prevents MDM 2 nucleocytoplasmic shuttling and thus stabilizes p 53 by attenuating MDM 2 mediated degradation , we studied the relationship of p14ARF epigenetic silencing to the expression and localization of MDM 2 and p 53 . ^^^ Cancer cell lines with an unmethylated p14ARF promoter showed strong nuclear expression of MDM 2 , whereas in a colorectal cell line with p14ARF hypermethylation associated inactivation , MDM 2 protein was also seen in the cytosol . ^^^ MDM 2 expression patterns revealed that lack of p14ARF promoter hypermethylation was associated with tumors showing exclusive nuclear MDM 2 staining , whereas MDM 2 cytosolic staining was frequently observed in neoplasms with aberrant p14ARF methylation . ^^^ Taken together , these data support that epigenetic silencing of p14ARF by promoter hypermethylation is a key mechanism in the disturbance of the MDM 2 nuclear localization in human cancer . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The INK4a / ARF locus on chromosome 9p21 encodes two gene products that are involved in cell cycle regulation through inhibition of CDK 4 mediated RB phosphorylation ( p16INK4a ) and binding to MDM 2 leading to p 53 stabilization ( p14ARF ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Stabilization of p 53 by p14ARF without relocation of MDM 2 to the nucleolus . ^^^ The alternative product of the human INK4a / ARF locus , p14ARF , has the potential to act as a tumour suppressor by binding to and inhibiting the p 53 antagonist MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Genetic alterations of the p14ARF hdm 2 p53 regulatory pathway in breast carcinoma . ^^^ The amplification and overexpression of HDM 2 plays a role in tumorigenesis via inactivation of p 53 dependent cell cycle arrest . p14ARF , an alternate transcript of the INK4A tumor suppressor locus , prevents hdm 2 induced transcriptional silencing of p 53 by binding hdm 2 . ^^^ The role of this p14ARF hdm 2 p53 regulatory pathway in breast carcinoma is unknown . ^^^ We hypothesized that p14ARF mutations and HDM 2 gene amplification may be alternative mechanisms of p 53 inactivation in breast cancer . ^^^ Mutational analysis of TP 53 ( exons 5 9 ) and exon 1beta of pl4ARF was performed by PCR SSCP and putative mutations were confirmed by sequencing . p14ARF mRNA expression was evaluated by RT PCR and the presence of HDM 2 gene amplification by differential PCR . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We therefore investigated the p14ARF MDM 2 p53 pathway in BL cell lines . p14ARF was expressed and localized to nucleoli in all BL carrying mutant p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We propose that high levels of Mdm 2 activity resulting from loss of p14ARF , and high levels of Mdm 2 protein resulting from activated Ras prevent accumulation of functional p 53 during infection of tumor cells that retain wild type p53 . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Different effects of p14ARF on the levels of ubiquitinated p 53 and Mdm 2 in vivo . ^^^ The p14ARF tumour suppressor has been shown to inhibit degradation of p 53 mediated by Mdm 2 . ^^^ Here we have compared the effects of p14ARF overexpression on the in vivo ubiquitination of p 53 and Mdm 2 . ^^^ We report that the inhibition of the Mdm 2 mediated degradation of p 53 by p14ARF is associated with a decrease in the proportion of ubiquitinated p 53 . ^^^ The levels of polyubiquitinated p 53 decreased preferentially compared to monoubiquitinated species . p14ARF overexpression increased the levels of Mdm 2 but it did not reduce the overall levels of ubiquitinated Mdm 2 in vivo . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Disruptions of the p 16 CDK4 / cyclin D 1 pRb pathway ( RB pathway ) and the p14ARF MDM 2 p53 pathway ( p 53 pathway ) are important mechanisms in the development of human malignancies . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Further , 50 % ( 10 / 20 ) of anaplastic oligodendrogliomas showed alterations in the TP 53 pathway through promoter hypermethylation or homozygous deletion of the p14ARF gene and , less frequently , through TP 53 mutation or MDM 2 amplification . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Aberrant expression of pRb , p 16 , p14ARF , MDM 2 , p 21 and p 53 in stage 1 adenocarcinomas of the lung . ^^^ In regard to the p 53 pathway , the frequency of immunohistochemical positivity was 8 % for p14ARF , 64 % for MDM 2 , 20 % for p 53 and 24 % for p 21 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Cirrhotic livers reveal genetic changes in the MDM 2 P14ARF system of cell cycle regulators . ^^^ The genesis of hepatocellular carcinoma is promoted by changes in the regulatory MDM 2 P14ARF system . ^^^ In the present study , 24 cirrhotic livers of alcohol , autoimmue disorder or HCV caused genesis were screened for MDM 2 P14ARF alterations at the level of protein , DNA and mRNA . ^^^ Using confocal laser scanning microscopy , the absence of MDM 2 and P14ARF expression was detected in all samples except three HCV infected livers ( four livers ) which contained hepatocytes overexpressing MDM 2 ( P14ARF ) protein . ^^^ In summary , this study gives first evidence for different types of MDM 2 and P14ARF alterations in cirrhotic livers . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The abnormal expression rate of p14ARF , MDM 2 , p 53 , and the p 53 pathway were 7 . 8 % ( 5 of 64 ) , 32 . 8 % ( 21 of 64 ) , 25 . 0 % ( 16 of 64 ) and 53 . 1 % ( 34 of 64 ) , respectively . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We observed that this inactivation results in part from the lack of expression of the MDM 2 inhibitor p14ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The CDKN 2 gene encodes two structurally different proteins : a cyclin dependent kinase inhibitor , p 16 , which regulates retinoblastoma protein ( pRb ) dependent G 1 arrest , and a cell cycle inhibitor , p14ARF , which blocks MDM 2 induced p 53 degradation resulting in an increase in p 53 levels that leads to cell cycle arrest . ^^^ To clarify the p14ARF status and the relationship between p16 / p14ARF and other cell cycle molecules in cervical carcinogenesis , immunohistochemical analysis of p 16 , p14ARF , p 53 and MDM 2 was performed on 65 samples of cervical and genital condylomatous and neoplastic lesions , including nine HPV negative tumors . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Adenovirus mediated p14ARF gene transfer cooperates with Ad5CMV p 53 to induce apoptosis in human cancer cells . p 14 ( ARF ) , a product of the INK4A / ARF locus , induces p 53 upregulation by neutralizing the effects of MDM 2 , a transcriptional target of p 53 that antagonizes its function . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We conclude that p14ARF del ( 77 84 ) has retained the ability to stabilize MDM 2 and p 53 , but that it is less potent than wt p14ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
P14ARF promotes accumulation of SUMO 1 conjugated ( H ) Mdm 2 . p14ARF tumour suppressor stabilises and activates p 53 by directly interacting with ( H ) Mdm 2 [ ( human ) murine double minute 2 homologue ] and inhibiting its E 3 ubiquitin ligase activity . ^^^ Here we demonstrate that p14ARF promotes accumulation of ( H ) Mdm 2 conjugated to the small ubiquitin like protein SUMO 1 . ^^^ Mutational analysis demonstrated that the N terminus of Mdm 2 is a target for p14ARF mediated SUMO conjugation . ^^^ SUMO modification requires residues 2 14 in p14ARF that interact with ( H ) Mdm 2 and residues 82 101 in exon 2 involved in nucleolar localisation of p14ARF . ^^^ These data suggest a novel role for p14ARF as a regulator of activity of ( H ) Mdm 2 , which could be related to its tumour suppressing activities . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Our previous and these results suggested that the expression level of MDM 2 protein is independent of the status of the p14ARF , p 53 , Rb genes . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The alpha transcript ( exons 1alpha , 2 , and 3 ) produces the p16INK4A cyclin dependent kinase inhibitor , while the beta transcript ( exons 1beta and 2 ) is translated as p14ARF , a stabilizing factor of p 53 levels through binding to MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The ARF ( p19ARF for the mouse ARF consisting of 169 amino acids and p14ARF for the human ARF consisting of 132 amino acids ) genes upregulate p 53 activities to induce cell cycle arrest and sensitize cells to apoptosis by inhibiting Mdm 2 activity . p 53 independent apoptosis also is induced by ectopic expression of p19ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
It has been found that Mdm 2 amplification was more frequent in GBM than in GBA and GBO , that p14ARF was inactivated in a high percentage of cases in the three tumor categories . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Here we describe the effect of a potent activator of the p 53 response , the nuclear export inhibitor leptomycin B , on Mdm 2 degradation and we provide evidence for the oligomerization of the p14ARF tumour suppressor and Mdm 2 inhibitor in response to oxidative stress . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The formation of p14ARF inclusions induces the parallel re localization p 53 and HDM 2 to these sites that are also targeted by PML bodies and proteasomes . ^^^ CONCLUSION : Our data show that co localization between p 53 , HDM 2 and p14ARF occurs at extranucleolar sites . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
BACKGROUND AND OBJECTIVES : Disruption of either the p14ARF mdm 2 p 53 or p16INK4A Rb 1 pathways produces a breakdown of regulatory mechanisms and creates a gateway for tumorigenesis . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The results show that in this setting , p14ARF promotes p 53 accumulation by increasing p 53 protein synthesis , in addition to its well characterized ability to oppose mdm 2 mediated degradation of p53 . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
PURPOSE : The growth suppressive genes p16INK4a and p14ARF located on the 9p21 gene cluster have active roles in the Rb and p 53 growth control pathways , respectively . p16INK4a is a cyclin dependent kinase inhibitor functioning upstream of Rb . p14ARF restrains cell growth by abrogating Mdm 2 inhibition of p 53 activity , thereby , facilitating p 53 mediated cell cycle arrest and apoptosis . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Next , nested PCR was performed for examining the expression of p 53 related genes , p21WAF1 , MDM 2 , p33ING1 and p14ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Clinical factors included FIGO stage , age , histopathologic type , and protein expression of p 53 , Rb , MDM 2 , p14ARF , p21WAF ( 1 ) / CIP ( 1 ) was determined by an immunohistochemical technique . ^^^ Histopathologic type and MDM 2 , p14ARF , p21WAF ( 1 ) / CIP ( 1 ) status did not show any prognostic value . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Distinct MDM 2 and P14ARF expression and centrosome amplification in well differentiated liposarcomas . ^^^ Expression of P14ARF , MDM 2 , and TP 53 proteins was assayed in the two WDL subtypes to establish whether distinct expression profiles correlated with cell ploidy . ^^^ Although a transcriptionally functional TP 53 was present in most tumors independent of their karyotype , type H cells were characterized by high levels of P14ARF and MDM 2 proteins . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
To determine the signaling elements regulating p 53 activity , DNA microarray of MCF+FIR using sham FIR MCF 7 cells as a reference demonstrated that the mRNA of p 21 , MDM 2 , and p14ARF was up regulated . ^^^ In agreement with MDM 2 inhibition , MDM 2 inhibitory protein p14ARF was increased in MCF+FIR cells . ^^^ In summary , these results demonstrate that up regulation of p14ARF paralleled with MDM 2 inhibition contributes to p 53 accumulation in the nucleus and causes a high responsiveness of p 53 in chronic IR treated breast cancer cells . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Taken together , the expression of the p 53 regulators mdm 2 and p14ARF are altered in AML , and low p14ARF levels indicate a poor prognosis . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In contrast , in these cells , IPTG dependent induction of p14ARF , which sequesters MDM 2 away from p 53 , does not lead to detectable phosphorylation of any of the five N terminal serine residues tested ( 6 , 9 , 15 , 20 , 37 ) . ^^^ However , the increase of p 21 and mdm 2 mRNAs was indistinguishable following treatment with adriamycin or induction of p14ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Shortly after irradiation , p14ARF binds p 53 independently of MDM 2 . ^^^ As nuclear pools of p 53 decline , endogenous p14ARF co immunoprecipitates with MDM 2 and is localized within the nucleolus . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Importantly , the tumor suppressor p14ARF compromises the Hdm 2 YY1 interaction , which is important for YY 1 regulation of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Expression of tumor suppressor gene product p14ARF in endometrioid adenocarcinoma of the uterine corpus . p 14 activates p 53 by inhibiting MDM 2 expression and arrests the cell cycle in G 1 and G2 / M . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In vitro , nuclear p14ARF binds Hdm 2 to block Hdm 2 dependent nucleocytoplasmic shuttling of p 53 , which is required before cytoplasmic degradation of p 53 . p14ARF is negatively regulated by p 53 and through p 53 independent pathways . ^^^ Previously , immunohistochemical expression of cytoplasmic p14ARF , p 53 and Hdm 2 has been described . ^^^ HER 2 ( c erbB2 / neu ) predicts prognosis and interacts with the p14ARF / Hdm2 pathway to inactivate p14ARF and to influence Hdm 2 activity and localisation . ^^^ Increasing levels of cytoplasmic p14ARF were associated with nuclear and cytoplasmic Hdm 2 expression ( P < 0 . 001 ) . ^^^ The association between HER 2 positivity and nuclear p14ARF ( P = 0 . 038 ) , as well as nuclear Hdm 2 ( P = 0 . 019 ) , reflects the in vitro findings of HER 2 interaction with the ARF / Hdm2 pathway . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Dysfunction of p 53 pathway in human colorectal cancer : analysis of p 53 gene mutation and the expression of the p 53 associated factors p14ARF , p33ING1 , p21WAF1 and MDM 2 . ^^^ In this study , we examined the expressions of p33ING1 , p14ARF , MDM 2 and p21WAF1 mRNA in 25 advanced colorectal cancers by quantitative RT PCR method , and compared the expression levels of p33ING1 , p14ARF , p21WAF1 and MDM 2 in relation to p 53 status in the tumors . ^^^ Interestingly , in eight cases with p 53 wild type gene , 6 cases ( 75 % ) showed a marked down regulation of p14ARF mRNA , and three cases ( 37 . 5 % ) over expressed MDM 2 mRNA . ^^^ Only one case with wild type p 53 gene showed normal level expression of p 53 regulatory factors ( p33ING1 , p14ARF , and MDM 2 ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Alteration of the MDM 2 p73 P14ARF pathway related to tumour progression during urinary bladder carcinogenesis . ^^^ Since the prospective clinical outcome can not be reliably predicted on histopathological grounds , we analysed the mRNA expression of the MDM 2 p73 P14ARF tumour surveillance pathway in an attempt to detect alterations of gene activity , allowing a better understanding of the mechanisms responsible for conversion of low to high malignant TCC . ^^^ The MDM 2 p73 P14ARF pathway was dominated by the MDM 2 gene , the mRNA expression of which proved to be significantly ( 5 fold ) lower in advanced high grade , high stage than in superficial low grade , low stage TCC . ^^^ An analysis of the effects of lifestyle and occupational bladder cancer risk factors revealed that TCC of smokers showed a 2 fold elevated expression of MDM 2 mRNA and an approximately 2 fold lower expression of P14ARF mRNA , whereas the activity of the p 73 gene was unchanged . ^^^ Our findings suggest that an alteration in the MDM 2 p73 P14ARF pathway is involved in the progression of bladder cancer to a more malignant and aggressive form . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Wild type p 53 overexpression and its correlation with MDM 2 and p14ARF alterations : an alternative pathway to non small cell lung cancer . ^^^ PATIENTS AND METHODS : We performed gene and protein alteration studies on p 53 and its upstream effectors , MDM 2 and p14ARF , in tumors from 94 non small cell lung cancer ( NSCLC ) patients . ^^^ CONCLUSION : Our data suggest that immunopositivity of p14ARF together with a low expression of MDM 2 contributes to accumulation of the wild type p 53 , and that deregulation of the p 53 MDM2 p14ARF pathway is important in the pathogenesis and outcome of a subset of NSCLC . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In particular , we demonstrate that p14ARF interacts with the SUMO E 2 conjugating enzyme , Ubc 9 and enhances the sumoylation of its binding partners , hdm 2 , E2F 1 , HIF 1alpha , TBP 1 and p120E4F . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
This pathway was recapitulated by deregulated Wnt / T cell factor signaling , with elevation of the tumor suppressor p14ARF , and reduced expression of the p 53 antagonist , MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
To address this , we have investigated the transcriptional activity of p 53 in a panel of renal cell carcinoma cell lines and the contribution of MDM 2 and p14ARF to p 53 regulation . ^^^ We have found that p 53 is functional in p 53 wild type renal cell carcinoma cells and that this activity is significantly regulated by MDM 2 and to a much lesser extent by p14ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Alterations of the p14ARF p 53 MDM2 pathway in oral squamous cell carcinoma : MDM 2 overexpression is a common event . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Quantity and stability of the MDM 2 protein is regulated by p 73 , p 53 , TSG 101 , p14ARF and Ras Raf MEK ERK pathway . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Analysis of mRNA and protein levels in melanomas with 12q14 amplification demonstrated overexpression of target genes CDK 4 and MDM 2 without loss of CDKN2A P 16 ( P16INK4A ) or CDKN2A P14ARF ( P14ARF ) expression , important regulators of the RB 1 and TP 53 pathways , which are commonly lost or mutated in melanoma . ^^^ These results suggest that coamplification of CDK 4 and MDM 2 may substitute for loss of P16INK4A and P14ARF function in a subset of melanomas . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The nucleolar ARF protein binds to MDM 2 to activate the growth suppressive functions of p 53 , but can also exert its tumor suppressor activity independently of p 53 , through mechanisms involving other regulators : in that manner , p14ARF has been shown to inhibit the transcriptional activity of E2F1 in vitro , suggesting that the two pathways intersect with one another . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Whereas p16Ink4a is an inhibitor of cyclin D dependent kinases , p19Arf ( p14ARF in humans ) antagonizes the E 3 ubiquitin protein ligase activity of Mdm 2 to activate p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Regulation of the p14ARF Mdm 2 p53 pathway : an overview in breast cancer . ^^^ Mdm 2 is a mediator for the function of both p14ARF and p 53 . ^^^ In this review article factors including Pokemon , Geminin , Twist , and Apigenin , which control the action of individual proteins in the p14ARF Mdm 2 p53 pathway in breast cancer as well the consequences of mutation 7 of p 53 are discussed . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The Ink4a tumor suppressor gene product , p19Arf , interacts with MDM 2 and neutralizes MDM 2 ' s inhibition of p 53 . ^^^ Here we show that p19Arf potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p 53 is neutralized by viral oncoproteins and dominant negative mutants but not by the p 53 antagonist MDM 2 . ^^^ This finding , coupled with the observations that p19Arf and MDM 2 physically interact and that p19Rrf blocks MDM 2 induced p 53 degradation and transactivational silencing , suggests that p19Arf functions mechanistically to prevent MDM 2 ' s neutralization of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The inhibitory mechanism of p19ARF has begun to be elucidated by the finding that the protein has the ability to bind the mdm 2 oncoprotein . mdm 2 is implicated in the degradation of p 53 and its functional inactivation . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The INK4a / ARF locus sits at the nexus of these two growth control pathways , by virtue of its ability to generate two distinct products : the p16INK4a protein , a cyclin dependent kinase inhibitor that functions upstream of RB ; and the p19ARF protein , which blocks MDM 2 inhibition of p 53 activity . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p19ARF protein is translated from an alternative transcript of the p16INK4a gene and regulates G 1 and G 2 phase of the cell cycle by degradation of the MDM 2 protein . p16INK4a and p15INK4b gene homozygous deletions occur mostly in acute lymphoblastic leukemia , ATL secondary to HTLV 1 infection , and some lymphoma . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The two gene products of the CDKN2A gene , p 16 and p19ARF , have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis , the RB 1 pathway and the p 53 pathway . p 16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D dependent kinases , whereas p19ARF targets MDM 2 , a p 53 inhibitory protein , for degradation . ^^^ We investigated 37 DLCL for aberrations of p 15 , p 16 , p19ARF , MDM 2 , and p 53 at the epigenetic , genetic and / or protein levels . ^^^ Twenty three ( 62 % ) tumours had alterations of one or more p 53 pathway components ( p 53 , p19ARF and MDM 2 ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p19ARF product of the INK4a / ARF locus is induced in response to potentially oncogenic hyperproliferative signals and activates p 53 by interfering with its negative regulator , Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
MDM 2 induced apoptosis is partially reverted by transient transfection with p 53 and p19ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Opposing effects of Ras on p 53 : transcriptional activation of mdm 2 and induction of p19ARF . ^^^ Mdm 2 induced by activated Raf degrades p 53 in the absence of the Mdm 2 inhibitor p19ARF . ^^^ In primary cells , Raf also activates the Mdm 2 inhibitor p19ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Degradation of p 53 was independent of both MDM 2 and p19ARF , regulators of p 53 stability in mammalian cells , but required an extended region of E4orf6 from residues 44 to 274 , which appeared to possess three separate biological functions . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Alternative and aberrant messenger RNA splicing of the mdm 2 oncogene in invasive breast cancer . mdm 2 is part of a complex mechanism that regulates the expression of p 53 as well as the function of Rb , p19ARF , and other genes . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Phosphorylation of MDM 2 enhances its nuclear localization and its interaction with p 300 , and inhibits its interaction with p19ARF , thus increasing p 53 degradation . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Finally , p19ARF was dramatically induced by TH , and although this protein can stabilize p 53 by sequestering mdm 2 , we found no increase in p 53 protein up to 48 h of treatment . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Loss of p19ARF enhances the defects of Mdm 2 overexpression in the mammary gland . ^^^ These phenotypes in the mammary epithelia of the transgenic mice are not dependent on either p 53 or the transcription factor E2F1 , as mice null for these genes carrying the BLGmdm 2 transgene exhibit similar defects to mice carrying the BLGmdm 2 transgene alone . p19ARF , an alternative splice product of the INK4a / ARF locus , has been shown to interact directly with MDM 2 . ^^^ Therefore , BLGmdm 2 transgenic mice null for p19ARF were created to gain insight into the mechanism by which mdm 2 overexpression disrupts the cell cycle . ^^^ Thus , the absence of p19ARF in this in vivo system enhanced the defect caused by mdm 2 overexpression . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Stabilization of p 53 does not depend on p19Arf interaction with mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Similarly , E2F1 dependent induction of p19ARF antagonizes the ability of mdm 2 to degrade p 53 , leading to p 53 stabilization and potentially p 53 mediated apoptosis or cell cycle arrest . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Cooperativity of p19ARF , Mdm 2 , and p 53 in murine tumorigenesis . ^^^ The p19ARF gene product responds to oncogenic stresses by interfering with the inhibitory effects of Mdm 2 on p 53 , thus enhancing p 53 activity and its antiproliferative functions . ^^^ To examine the tumorigenic cooperativity of p19ARF , Mdm 2 , and p 53 in vivo , p19ARF deficient mice were crossed first to p 53 deficient mice and then to Mdm 2 transgenic mice . ^^^ In the second cross between p19ARF deficient and Mdm 2 transgenic mice , cooperativity in tumor incidence between Mdm 2 overexpression and ARF deficiency was observed , consistent with the role of p19ARF in negatively regulating Mdm 2 activity . ^^^ These experiments further demonstrate in vivo the inter relationships of the p19ARF Mdm 2 p53 signaling axis in tumor suppression . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Although p19Arf binds to the Mdm 2 E3 ubiquitin protein ligase to activate p 53 , neither of these molecules regulates p19Arf turnover . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Activated Ras , operating through the Raf / MEK / ERK pathway , is known to regulate transcription of both Mdm 2 and its inhibitor p19ARF , resulting in opposing effects on the tumor suppressor protein p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The tumor suppressor p19ARF inhibits Mdm 2 , which restricts the activity of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In cultured cells , p19Arf decreased Pdgfrbeta and blocked Pdgf B driven proliferation independently of Mdm 2 and p 53 . ^^^ Our findings demonstrate a novel , p 53 and Mdm 2 independent function for p19Arf . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
MDM 2 and p19ARF are essential proteins in cancer pathways forming a complex with protein p 53 to control the transcriptional activity of protein p 53 . ^^^ However , it is still unclear that protein p 53 keeps its transcriptional activity when it forms the trimer with proteins MDM 2 and p19ARF . ^^^ We have observed mutual behaviors among genes p 53 , MDM 2 , p19ARF and their products on a computational model with hybrid functional Petri net ( HFPN ) which is constructed based on information described in the literature . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
This , along with the link that exists between p 53 and INK 4 suppressor pathways through ARF and MDM 2 , and the role of the universal cdk inhibitors ( the Cip / Kip family ) in these neoplasms deserve further investigation . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The expression of c myc , MDM 2 , c erbB 2 , EGFR , p 53 , p 14 ( ARF ) , p 16 ( INK 4 ) , p 21 ( WAF 1 ) and nm 23 was detected by immunohistochemical assay . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
INK4a , a critical element of the retinoblastoma gene pathway , binds to and inhibits the activities of CDK 4 and CDK 6 , while ARF , a critical element of the p 53 pathway , increases the level of functional p 53 via interaction with MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Whereas p 16 ( INK4a ) restrains cell growth through preventing phosphorylation of the retinoblastoma protein , p 19 ( ARF ) acts by attenuating Mdm 2 mediated degradation of p 53 , thereby stabilizing p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Through the use of shared coding regions and alternative reading frames two distinct proteins are produced : INK4a is a cyclin dependent kinase inhibitor whereas ARF binds the MDM 2 proto oncogene and stabilizes p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The prognostic significance of p 16 ( INK4a ) / p14 ( ARF ) locus deletion and MDM 2 protein expression in adult acute myelogenous leukemia . ^^^ Although p 16 ( INK4a ) and p 15 ( INK4b ) are involved in the phosphorylation of the retinoblastoma ( Rb ) protein , p 14 ( ARF ) interacts with the MDM 2 oncoprotein antagonizing its function as a suppressor of p 53 . ^^^ The role of deletions of p 16 ( INK4a ) / p14 ( ARF ) and p 15 ( INK4b ) and expressions of MDM 2 in myeloid leukemias and its influence on prognosis remain unclear . ^^^ CONCLUSIONS : The authors concluded that 1 ) deletions of p 16 ( INK4a ) / p14 ( ARF ) and / or p 15 ( INK4b ) occur with low incidence in patients with AML ; 2 ) patients with deletions of p 16 ( INK4a ) / p14 ( ARF ) and / or p 15 ( INK4b ) have a significantly shorter CR duration , EFS rate , and overall survival rate than do patients without deletions ; ( 3 ) overexpression of MDM 2 is common in AML and is associated with shorter CR duration and EFS rate . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Infection with Adp 16 ( INK4a ) and Adp 53 led to an increase in the level of mdm 2 in the SK OV 3 cell line only . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF ) nuclear overexpression in aggressive B cell lymphomas is a sensor of malfunction of the common tumor suppressor pathways . p 14 ( ARF ) , the alternative product from the human INK4a / ARF locus , antagonizes Hdm 2 and mediates p 53 activation in response to oncogenic stimuli . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
To elucidate the role of p53 / p16 ( INK4a ) / RB1 pathways in prostate carcinogenesis , we analyzed the p 14 ( ARF ) , p 16 ( INK4a ) , RB 1 , p 21 ( Waf 1 ) , p 27 ( Kip 1 ) , PTEN , p 73 , p 53 , and MDM 2 gene status of multiple areas within 16 histologically heterogeneous prostate carcinomas using methylation specific polymerase chain reaction , differential polymerase chain reaction , and immunohistochemistry . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In T HME cells , the expression of two p 53 regulated genes p 21 ( WAF ) and HDM 2 increased ( as in primary senescent HME cells ) , and was found to be further elevated as the function of p 53 was activated by treatment with DNA damaging agents . p 16 ( INK4a ) was shown to be significantly higher in the primary senescent HME and the early passage T HME cells when compared with the primary presenescent HME cells , with a dramatic repression of p 16 ( INK4a ) observed in the later passage T HME cells . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
TP 53 , CDKN2A ( p 16 ( INK4a ) ) , CDK 4 , MDM 2 , and EGFR . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In this study , we examined the effect of flavopiridol on a panel of glioma cell lines having different genetic profiles : five of six have codeletion of p 16 ( INK4a ) and p 14 ( ARF ) ; three of six have p 53 mutations ; and one of six shows overexpression of mouse double minute 2 ( MDM 2 ) protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In our study , we screened HCCs resulting from HCV infection ( 51 cases ) , HBV infection ( 26 cases ) or excess alcohol intake ( 23 cases ) for alterations in genes involved in the RB 1 pathway ( p 16 ( INK4a ) , p 15 ( INK4b ) , RB 1 , CDK 4 and cyclin D 1 ) , the p 53 pathway ( p 53 , p 14 ( ARF ) and MDM 2 ) and the Wnt pathway ( beta catenin , APC ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Immunohistochemistry was employed to detect the expression of p 16 ( INK4a ) , p 21 ( WAF 1 ) , p 33 ( ING1b ) , p 53 , p 57 ( KIP 2 ) , p 73 , mdm 2 , and ATM genes in tumor and adjacent tumor liver tissue , respectively . ^^^ Except p 16 ( INK4a ) , p 21 ( WAF 1 ) , and p 73 genes ( P > 0 . 05 ) , the expression of p 33 ( ING1b ) , p 53 , mdm 2 , ATM , and p 57 ( KIP 2 ) genes in HCC with portal vein invasion were higher than those in HCC without portal vein invasion ( p 33 ( ING1b ) , p 53 , mdm 2 , ATM , P < 0 . 01 ; p 57 ( KIP 2 ) , P < 0 . 05 ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Our results demonstrate that RCCs from patients living in the radio contaminated areas showed aberrant hypermethylation of p 14 ( ARF ) and p 16 ( INK4A ) genes , associated with increased p38MAPK , p 14 ( ARF ) , mdm 2 , cyclinD 1 and Ki 67 protein expression levels . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
METHODS : The expression levels of p 53 , murine double minute 2 ( MDM 2 ) , retinoblastoma protein ( pRb ) , cyclin D 1 , p 16 ( INK4a ) , and p 27 ( Kip 1 ) were investigated using immunohistochemical techniques ; p 53 mutations were studied by polymerase chain reaction ( PCR ) single strand conformation polymorphism , and mdm 2 amplification was analyzed using real time quantitative PCR . ^^^ RESULTS : Approximately 10 45 % of primary tumors presented alterations of p 53 , MDM 2 , cyclin D 1 , and pRb proteins ; most tumors lacked expression of p 16 ( INK4a ) and p 27 ( Kip 1 ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
EXPERIMENTAL DESIGN : We determined the mRNA expression of p 1 ( INK4A ) , p 14 ( ARF ) , CDK 4 , RB 1 , MDM 2 , TP 53 , and E2F1 by quantitative reverse transcription PCR in 38 cases of GISTs and correlated the findings with clinicopathologic factors , including mutation analysis of KIT and PDGFRA . ^^^ GISTs with low mRNA expression of the CDKN2A transcripts p 16 ( INK4A ) and p 14 ( ARF ) but high mRNA expression of CDK 4 , RB 1 , MDM 2 , TP 53 , and E2F1 were associated with aggressive clinical behavior and unfavorable prognosis , whereas GISTs with a low mRNA expression of CDK 4 , RB 1 , MDM 2 , TP 53 , and E2F1 were not . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Mutation of the p 53 gene , amplification of the MDM 2 gene , homozygous deletion , methylation status and mutation of the p 16 ( INK4a ) / p14 ( ARF ) genes were also investigated , using concordant paraffin embedded and frozen material . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Functional and physical interactions of the ARF tumor suppressor with p 53 and Mdm 2 . ^^^ Using insect cells infected with baculovirus vectors and NIH 3T3 fibroblasts infected with ARF retrovirus , we determined that mouse p 19 ( ARF ) can interact directly with p 53 , as well as with the p 53 regulator mdm 2 . ^^^ ARF can bind p 53 DNA complexes , and it depends upon functional p 53 to transcriptionally induce mdm 2 and the cyclin dependent kinase inhibitor p 21 ( Cip 1 ) , and to arrest cell proliferation . ^^^ In this setting , reintroduction of p 19 ( ARF ) restores p 53 ' s ability to induce p 21 ( Cip 1 ) and mdm 2 , implying that , in addition to stabilizing p 53 , ARF modulates p 53 dependent function through an additional mechanism . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The alternative product from the human CDKN2A locus , p 14 ( ARF ) , participates in a regulatory feedback loop with p 53 and MDM 2 . ^^^ In contrast , the product of the human CDKN2A beta transcript , p 14 ( ARF ) , activates a p 53 response manifest in elevated levels of MDM 2 and p 21 ( CIP 1 ) and cell cycle arrest in both G 1 and G2 / M . ^^^ As a consequence , p 14 ( ARF ) induced cell cycle arrest is p 53 dependent and can be abrogated by the co expression of human papilloma virus E 6 protein . p 14 ( ARF ) acts by binding directly to MDM 2 , resulting in the stabilization of both p 53 and MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Association of p 19 ( ARF ) with Mdm 2 inhibits ubiquitin ligase activity of Mdm 2 for tumor suppressor p 53 . ^^^ We further investigated whether the tumor suppressor p 19 ( ARF ) affects the ubiquitin ligase activity of Mdm 2 for p 53 . ^^^ The activity of p 19 ( ARF ) bound Mdm 2 was found to be lower than that of free Mdm 2 , suggesting that p 19 ( ARF ) promotes the stabilization of p 53 by inactivating Mdm2 . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Progress in the analysis of signalling to p 53 including phosphorylation cascades , and interactions with proteins such as mdm 2 and ARF are highlighted . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Disruption of the ARF Mdm 2 p53 tumor suppressor pathway in Myc induced lymphomagenesis . ^^^ In cultured primary mouse embryo fibroblasts , c Myc activates the p 19 ( ARF ) Mdm 2 p53 tumor suppressor pathway , enhancing p 53 dependent apoptosis but ultimately selecting for surviving immortalized cells that have sustained either p 53 mutation or biallelic ARF deletion . ^^^ Here we report that p 53 and ARF also potentiate Myc induced apoptosis in primary pre B cell cultures , and that spontaneous inactivation of the ARF Mdm 2 p53 pathway occurs frequently in tumors arising in Emu myc transgenic mice . ^^^ Many Emu myc lymphomas sustained either p 53 ( 28 % ) or ARF ( 24 % ) loss of function , whereas Mdm 2 levels were elevated in others . ^^^ About half of the tumors arising in ARF hemizygous or ARF nullizygous Emu myc transgenic mice also overexpressed Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Nucleolar Arf sequesters Mdm 2 and activates p 53 . ^^^ Here we show that Arf binds to the product of the Mdm 2 gene and sequesters it into the nucleolus , thereby preventing negative feedback regulation of p 53 by Mdm 2 and leading to the activation of p 53 in the nucleoplasm . ^^^ Arf and Mdm 2 co localize in the nucleolus in response to activation of the oncoprotein Myc and as mouse fibroblasts undergo replicative senescence . ^^^ These topological interactions of Arf and Mdm 2 point towards a new mechanism for p 53 activation . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Inhibition of MDM 2 expression using antisense oligonucleotide , inhibition of MDM 2 function by the tumor suppressor ARF or a MDM 2 deletion mutant result in the accumulation of nuclear p 53 . p 53 point mutants deficient in MDM 2 binding have increased nuclear localization . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Analysis of JNK , Mdm 2 and p 14 ( ARF ) contribution to the regulation of mutant p 53 stability . ^^^ Three mutant forms , which exhibit high expression levels , showed lower affinity for association with Mdm 2 and JNK in concordance with greater affinity to p 14 ( ARF ) , which is among the stabilizing p 53 molecules . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Nucleolar relocalization of Mdm 2 by ARF connotes a novel mechanism for preventing p 53 turnover and provides a framework for understanding how stress signals cooperate to regulate p 53 function . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The ARF tumor suppressor protein stabilizes p 53 by antagonizing its negative regulator , Mdm 2 ( Hdm 2 in humans ) . ^^^ Cooperative signals governing ARF mdm 2 interaction and nucleolar localization of the complex . ^^^ Both mouse p 19 ( ARF ) and human p 14 ( ARF ) bind to the central region of Mdm 2 ( residues 210 to 304 ) , a segment that does not overlap with its N terminal p 53 binding domain , nuclear import or export signals , or C terminal RING domain required for Mdm 2 E3 ubiquitin ligase activity . ^^^ The N terminal 37 amino acids of mouse p 19 ( ARF ) are necessary and sufficient for binding to Mdm 2 , localization of Mdm 2 to nucleoli , and p 53 dependent cell cycle arrest . ^^^ Although a nucleolar localization signal ( NrLS ) maps within a different segment ( residues 82 to 101 ) of the human p 14 ( ARF ) protein , binding to Mdm 2 and nucleolar import of ARF Mdm 2 complexes are both required for cell cycle arrest induced by either the mouse or human ARF proteins . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Stabilization of p 53 in response to stress is associated with inhibition of MDM 2 mediated degradation , which has been associated with phosphorylation of p 53 in response to DNA damage or activation of ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
BACKGROUND : The p 14 ( ARF ) protein encoded by the INK4a / ARF locus promotes degradation of the MDM 2 protein and thus prevents the MDM 2 mediated inhibition of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF ) MDM 2 loop in ex vivo and cultured adult T cell leukemia / lymphoma cells . ^^^ Because p 53 is part of a regulatory loop that also involves MDM 2 and p 14 ( ARF ) , the status of the latter proteins was also assessed in cultured or fresh ATLL cells . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The growth of explanted DMP 1 null mouse embryo fibroblasts ( MEFs ) is progressively retarded as cells are passaged in culture on defined transfer protocols ; but , unlike the behavior of normal cells , p 19 ( ARF ) , Mdm 2 , and p 53 levels remain relatively low and DMP 1 null MEFs do not senesce . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Induction of apoptosis in human esophageal cancer cells by sequential transfer of the wild type p 53 and E2F 1 genes : involvement of p 53 accumulation via ARF mediated MDM 2 down regulation . ^^^ Here we report that sequential transfer of the wild type p 53 and E2F 1 genes efficiently induces apoptosis in human esophageal cancer cells and that E2F 1 overexpression directly , activates expression of p 14 ( ARF ) , which inhibits MDM 2 mediated p 53 degradation , resulting in the stabilization of p 53 . ^^^ Tn and TE 8 with adenovirus vector expressing E2F 1 ( Ad E2F 1 ) enhanced mRNA and protein expression of ARF and decreased MDM 2 protein expression . ^^^ Transfection of ARF plasmid decreased MDM 2 protein expression , which in turn increased p 53 protein expression . ^^^ Moreover , Ad E2F 1 mediated ARF expression inhibited the up regulation of MDM 2 by overexpressed p 53 in TE 8 cells . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
By antagonizing Mdm 2 , a negative regulator of the p 53 tumor suppressor , ARF triggers a p 53 dependent transcriptional response that diverts incipient cancer cells to undergo growth arrest or apoptosis . ^^^ Lesions in the p 16 cyclin D CDK 4 Rb and ARF Mdm 2 p 53 pathways occur so frequently in cancer , regardless of patient age or tumor type , that they appear to be part of the life history of most , if not all , cancer cells . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Deletion analysis of MDM 2 indicated that the sites of modification fall into two clusters which map respectively within the N terminal region encompassing the p 53 binding domain and nuclear export sequence , and the central acidic domain that mediates p 14 ( ARF ) binding , p 53 ubiquitination and cytoplasmic shuttling . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p 19 ( ARF ) tumor suppressor antagonizes Mdm 2 to induce p 53 dependent cell cycle arrest . ^^^ Individual TKO ( triple knock out ) mice nullizygous for ARF , p 53 , and Mdm 2 develop multiple tumors at a frequency greater than those observed in animals lacking both p 53 and Mdm 2 or p 53 alone , demonstrating that p 19 ( ARF ) can act independently of the Mdm 2 p53 axis in tumor surveillance . ^^^ Thus , in the absence of Mdm 2 , p 19 ( ARF ) interacts with other targets to inhibit cell proliferation . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
This inhibitory activity of MDM 2 on p 53 acetylation is in turn abrogated by tumor suppressor p 19 ( ARF ) , indicating that regulation of acetylation is a central target of the p 53 MDM2 p 19 ( ARF ) feedback loop . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Although oncogenic ras produced a substantial increase in both nucleolar and nucleoplasmic p 19 ( ARF ) , Mdm 2 did not relocalize to the nucleolus or to nuclear bodies but remained distributed throughout the nucleoplasm . ^^^ This result suggests that p 19 ( ARF ) can activate p 53 without overtly affecting Mdm 2 subcellular localization . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF is part of an ARF mdm 2 p53 network that exerts a negative control on hyperproliferative signals emanating from oncogenic stimuli . ^^^ Moreover , we show that mdm 2 is required for the modulation of E2F1 activity by ARF . ^^^ Beside the well known p 53 and mdm 2 partners , these results identify E2F1 as a new ARF target . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Through two novel mechanisms , Arf inhibits the oncoprotein Hdm 2 , a negative regulator of p 53 . ( 1 ) Arf inhibits the E 3 ubiquitin ligase activity of Hdm 2 that leads to p 53 degradation , and ( 2 ) Arf sequesters Hdm 2 within nucleoli . ^^^ Fundamental to these processes are interactions between Arf and Hdm 2 . ^^^ Here we show that a peptide containing the 37 N terminal amino acids of mouse Arf ( mArfN 37 ) localizes to nucleoli , sequesters Hdm 2 within nucleoli , and causes cell cycle arrest . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Control of p 53 ubiquitination and nuclear export by MDM 2 and ARF . p 53 and ARF INK4a are the two most frequently altered loci in human tumors . ^^^ Responding to oncogenic signal activated cell hyperproliferation , ARF mediated antagonism of MDM 2 inhibition results in p 53 becoming active and its protein levels rising . ^^^ The biochemical mechanisms of ubiquitination and nuclear export that underlie the functions of ARF and MDM 2 in p 53 control continue to emerge . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Phosphorylation of MDM 2 at Thr 216 both weakens its interaction with p 53 and modestly augments its binding to p 19 ( ARF ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The interaction between MDM 2 and hsp 90 is disrupted by the 2A10 antibody , which recognizes a site on MDM 2 important for binding to alternative reading frame ( ARF ) . ^^^ Expression of mutant p 53 prevents MDM 2 from binding ARF and accumulating in the nucleolus in an hsp 90 dependent fashion . ^^^ These results suggest that hsp 90 recruited by mutant p 53 conceals the ARF binding site on MDM 2 and inhibits its ubiquitin protein isopeptide ligase function , resulting in the stabilization of both mutant p 53 and MDM2 . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Although there is no detectable interaction or co localization of endogenous ARF ( nucleoli ) and MDM 2 ( nucleoplasm ) in PyREF 52 cells , expression of transfected ectopic ARF results in an MDM2 / ARF interaction and sequestration of MDM 2 into the nucleoli . ^^^ Sequestration of MDM 2 by ARF in the nucleoli is not essential for a p 53 response in REF 52 cells as activation of Raf in REF52Raf ER cells results in an ARF induced p 53 mediated cell cycle block in the absence of a detectable ARF MDM 2 interaction . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Eighty percent of lymphomas arising in wild type E mu myc transgenics have alterations in the ARF Mdm 2 p53 tumor suppressor pathway characterized by deletions in ARF , mutations or deletions of p 53 , and overexpression of Mdm 2 . ^^^ Furthermore , Mdm 2 was overexpressed at the same frequency in lymphomas irrespective of Bax status , suggesting that Bax resides in a pathway separate from ARF and Mdm 2 . ^^^ Thus , the loss of Bax eliminates the selection of p 53 mutations and deletions , but not ARF deletions or Mdm 2 overexpression , during Myc induced tumorigenesis , formally demonstrating that Myc induced apoptotic signals through ARF / Mdm2 and p 53 must bifurcate : p 53 signals through Bax , whereas this is not necessarily the case for ARF and Mdm2 . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
There was no overexpression of MDM 2 , and loss of p 14 ( ARF ) expression and p 53 mutation were infrequent events . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The ability of MDM 2 to inhibit p 53 functions is antagonized by the ARF oncosuppressor protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Defining the molecular basis of Arf and Hdm 2 interactions . ^^^ Understanding the interaction of Arf and Hdm 2 has recently become a central issue in cancer biology . ^^^ In response to hyperproliferative signals , p 14 ( Arf ) stabilizes p 53 by binding to Hdm 2 and inhibits the ubiquitination and subsequent proteosome dependent degradation of p 53 . ^^^ The medical importance of the Arf Hdm 2 p53 regulatory system is highlighted by the finding that either p 53 or p 14 ( Arf ) are lost or modified in virtually all human cancers . ^^^ Isolated Arf and Hdm 2 domains are dynamically disordered in solution , yet they retain the ability to interact in vitro and in cellular assays . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF function does not require p 53 stabilization or Mdm 2 relocalization . ^^^ It is generally accepted that the ARF tumor suppressor induces p 53 dependent growth arrest by sequestering the p 53 antagonist Mdm 2 in the nucleolus . ^^^ Previous mutagenic studies of murine ARF suggested that residues 1 through 14 and 26 through 37 were critical for Mdm 2 binding , while the latter domain also governed ARF nucleolar localization . ^^^ Those observations stood in apparent contrast to the ability of wild type ARF to block growth in some cells without relocalizing endogenous Mdm 2 to nucleoli . ^^^ Together , these data show a lack of correlation between ARF activity and Mdm 2 relocalization , suggesting that additional events other than Mdm 2 import are required for ARF function . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
These proteins are involved in two different metabolic pathways , the first including p 53 , represented by E2F , ARF , MDM 2 , p 53 , p21Waf1 , and the second concerning pRb and p16INK4a . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Nucleolar p 14 ( ARF ) overexpression in Reed Sternberg cells in Hodgkin ' s lymphoma : absence of p 14 ( ARF ) / Hdm2 complexes is associated with expression of alternatively spliced Hdm 2 transcripts . ^^^ Because the existence of nucleolar complexes between p 14 ( ARF ) and Hdm 2 has been described as having a critical effect on p 53 function by inhibiting its degradation , we analyzed the expression and subcellular localization of these proteins in 52 cases and in Hodgkin ' s cell lines . ^^^ The majority of Hodgkin ' s samples showed a strong nucleolar expression of p 14 ( ARF ) that was not associated with Hdm 2 . ^^^ The different localization of Hdm 2 ( nucleoplasm ) and p 14 ( ARF ) ( nucleoli ) observed in Hodgkin ' s tumors and cell lines is associated with the presence of short alternatively spliced transcripts of Hdm 2 lacking the ARF binding region and the nuclear export signal . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p 14 ( ARF ) protein directly inhibits the MDM 2 oncoprotein , which mediates degradation of the p 53 protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Despite the absence of the p 53 binding domain , growth inhibition remained strictly p 53 dependent ( but not p 19 ( Arf ) dependent ) and could be overcome by full length Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We further showed that the effects of IGF 1 on mdm 2 transcription and on MDM2 / p19 ARF association were mediated by the p 38 MAPK pathway . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Strong p 53 expression and apoptosis can be achieved in A 549 cells using a p 53 mutant resistant to degradation by MDM 2 or by coexpression of ARF . ^^^ The results suggest that enhanced MDM 2 activity attributable to loss of ARF contributes to p 53 resistance . ^^^ Surprisingly , tumor cell lines with MDM 2 gene amplification are still deficient for ARF expression , suggesting that MDM 2 amplification does not substitute for ARF inactivation during tumor development . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Mdm 2 overexpression and p 14 ( ARF ) inactivation are two mutually exclusive events in primary human lung tumors . ^^^ Interestingly , a highly significant inverse relationship was detected between p 14 ( ARF ) loss and Mdm 2 overexpression either in NSCLC ( P=0 . 0089 ) or in NE lung tumors ( P < 0 . 0001 ) . ^^^ Furthermore , a Mdm2 / p14 ( ARF ) > 1 ratio was correlated with a high grade phenotype among NE tumors overexpressing Mdm 2 ( P=0 . 0021 ) . ^^^ Taken together , these data strongly suggest that p 14 ( ARF ) and Mdm 2 act on common pathway ( s ) to regulate p 53 and / or pRb dependent or independent functions and that the Mdm 2 : p 14 ( ARF ) ratio might act as a rheostat in modulating the activity of both proteins . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF facilitates growth arrest through the p 53 pathway by hindering the down regulation of p 53 activity mediated by MDM 2 , through the formation of a protein complex with MDM 2 . ^^^ A mutational analysis of p 14 ( ARF ) indicates that the E2F 1 and MDM 2 binding domains can be distinguished . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
By inactivating Mdm 2 , p 19 ( ARF ) upregulates p 53 activities to induce cell cycle arrest and sensitize cells to apoptosis in the presence of collateral signals . ^^^ It has also been demonstrated that cell cycle arrest is induced by overexpressed p 19 ( ARF ) in p 53 deficient mouse embryonic fibroblasts , only in the absence of the Mdm 2 gene . ^^^ Also , in primary mouse embryonic fibroblasts ( MEFs ) lacking p53 / ARF , p 53 independent apoptosis is induced irrespective of Mdm 2 status by expression of p 19 ( ARF ) . ^^^ In agreement , p 19 ( ARF ) mediated apoptosis in U2OS cells , but not in Saos 2 cells , was attenuated by coexpression of Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p 14 ( ARF ) protein interacts with the MDM 2 protein , neutralizing MDM 2 mediated degradation of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Enhancement of p 53 expression after disruption of p 21 ( WAF 1 ) resulted from a stabilization of p 53 , which correlated with an increased expression of the tumor suppressor p 14 ( ARF ) , an inhibitor of the ubiquitin ligase activity of Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The current prevailing model proposes that p 19 ( ARF ) activates p 53 function by antagonizing its degradation by MDM 2 . ^^^ It was , however , recently shown that stabilization of p 53 by p 14 ( ARF ) occurs independent of the relocalization of MDM 2 to the nucleolus . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Cyclin G 1 interacted directly with MDM 2 and promoted the formation of the ARF / MDM2 complex within the initial 24 h period following DNA damage . ^^^ CONCLUSION : These results suggest that cyclin G 1 stabilizes and promotes the degradation of p 53 protein by associating , respectively , with MDM 2 complexes containing ARF and PP2A . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Adp 14 ( ARF ) mediated expression of p 14 ( ARF ) also resulted in a considerable increase in the amounts of p 53 and its target proteins , p 21 ( WAF 1 ) and MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
An important activity of ARF is regulation of p 53 stability and function through binding to the mdm 2 protein . ^^^ By sequestering mdm 2 , ARF may promote growth suppression through the Rb pathway as well because mdm 2 can bind to Rb and attenuate its function . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Furthermore , MDMX may complement MDM 2 in regulating p 53 during embryonic development due to its ability to inhibit p 53 in the presence of ARF . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The tumor suppressor protein ARF inhibits MDM 2 to activate and stabilize p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Cyclin G 1 has growth inhibitory activity linked to the ARF Mdm 2 p53 and pRb tumor suppressor pathways . ^^^ We tested its effects on growth and involvement in the ARF Mdm 2 p53 tumor suppressor pathway . ^^^ We show that cyclin G 1 interacts with ARF , Mdm 2 , and p 53 in vitro and in vivo . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Further understanding of this mechanism may lead to novel strategies for p 53 stabilization and tumor suppression in cancers , even those with absent ARF or high MDM 2 expression . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The tumor suppressor p 19 ( Arf ) ( p 14 ( ARF ) in humans ) , encoded by the Ink4a / Arf locus , is mutated , deleted , or silenced in many forms of cancer . p 19 ( Arf ) induces growth arrest by antagonizing the activity of the p 53 negative regulator , Mdm 2 , thereby inducing a p 53 transcriptional response . p 19 ( Arf ) can also inhibit cell cycle progression of mouse embryo fibroblasts lacking Cip 1 or lacking both Mdm 2 and p 53 , although in the absence of p 53 , arrest occurs more slowly . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p 19 ( Arf ) tumor suppressor , a nucleolar protein , binds to Mdm 2 to induce p 53 dependent cell cycle arrest . ^^^ Arf also prevents the proliferation of cells lacking Mdm 2 and p 53 , albeit less efficiently . ^^^ Evolution may have linked a primordial nucleolar Arf function to Mdm 2 and p 53 , creating a more efficient checkpoint signaling pathway for coordinating ribosomal biogenesis and cell cycle progression . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Interactive pathway of ARF mdm 2 p53 ] . ^^^ ARF participates in the regulation of mdm 2 p53 pathway by mdm 2 . ^^^ Here is a review of ARF mdm 2 p53 interacting pathway . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF stabilizes and activates p 53 by negating the effects of mdm 2 on p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Most of the time , the inactivation of the P 53 pathway results from a loss of function of the p 53 protein , secondary to mutation and / or deletion of the P 53 gene ; It may also result of the amplification of the MDM 2 gene and of the inactivation of the arf protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The inhibition of HDM 2 activity by L 11 shows some similarity to the previously described activity of ARF , and expression of either ARF or L 11 can induce a p 53 response . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Mitogenic signals activate p 53 by induction of ARF expression , which inhibits p 53 ubiquitination by MDM 2 . ^^^ This effect is stimulated by ARF and correlates with the ability of ARF to bind MDM 2 . ^^^ Promotion of MDM 2 mediated MDMX ubiquitination requires the N terminal domain of ARF , which normally inhibits MDM 2 ubiquitination of p 53 . ^^^ Increase of MDM 2 and ARF levels by DNA damage , recombinant ARF adenovirus infection , or inducible MDM 2 expression leads to proteasome mediated down regulation of MDMX levels . ^^^ The ARF tumor suppressor differentially regulates the ability of MDM 2 to promote p 53 and MDMX ubiquitination and activates p 53 by targeting both members of the MDM 2 family . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Mdm 2 independent repression of NF kappa B transactivation by the ARF tumor suppressor . ^^^ One mechanism by which a cell affords protection from the transforming effects of oncogenes is via the action of the tumor suppressor , ARF , which activates p 53 by inactivating Mdm 2 . ^^^ Here we find that ARF inhibits NF kappa B function and its antiapoptotic activity independent of Mdm 2 and p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Mdm 2 is a nucleoplasmic and nucleolar protein interacting with p 53 and alternative reading frame ( ARF ) tumor suppressor proteins . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
MDM 2 ARF complex regulates p 53 sumoylation . ^^^ Ubiquitination of p 53 is regulated by ARF , which binds to MDM 2 and inhibits its E 3 ligase function . ^^^ Overexpression of MDM 2 increases the level of p 53 sumoylation , which is further stimulated by expression of ARF . ^^^ An MDM 2 deletion mutant ( MDM 2 ( Delta 222 437 ) ) with activated cryptic nucleolar localization signal also targets p 53 to the nucleolus and efficiently promotes p 53 sumoylation in the absence of ARF . ^^^ Direct targeting of p 53 to the nucleolus enhances its sumoylation in an MDM 2 and ARF dependent fashion . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Blockage of p 53 degradation pathways either by overexpression of ARF or interruption of MDM 2 : p 53 interaction is effective in inducing p 53 triggered tumor cell death . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
These included 3 genes coding for proteins in the p 53 pathway ( i . e . , TP 53 , p 14 ( ARF ) , and MDM 2 ) , 4 in the Rb 1 pathway ( i . e . , CDKN2A , CDKN2B , RB 1 , and CDK 4 ) , as well as PTEN and epidermal growth factor receptor . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Abundant expression of spliced HDM 2 in Hodgkin lymphoma cells does not interfere with p 14 ( ARF ) and p 53 binding . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Nucleotide binding by the Mdm 2 RING domain facilitates Arf independent Mdm 2 nucleolar localization . ^^^ Although nucleotide binding is not required for Mdm 2 E3 ubiquitin ligase activity , we show that nucleotide binding defective P loop mutants are impaired in p 14 ( ARF ) independent nucleolar localization both in vivo and in vitro . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
L 11 binds a central region in HDM 2 that is distinct from the ARF binding site . ^^^ We show that the functional consequence of L 11 HDM2 association , like that with ARF , results in the prevention of HDM 2 mediated p 53 ubiquitination and degradation , subsequently restoring p 53 mediated transactivation , accumulating p 21 protein levels , and inducing a p 53 dependent cell cycle arrest by canceling the inhibitory function of HDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
This decrease was reversed by the proteasome inhibitors MG 132 and lactacystin , by p 19 ( arf ) , and by small interfering RNA ( siRNA ) against MDM 2 . p21waf1 / cip1 bound to MDM 2 in vitro and in cells . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Unlike the nucleoplasmic MDM 2 and p 53 , ARF localizes in the nucleolus . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Mdm 2 regulates p 53 independently of p 19 ( ARF ) in homeostatic tissues . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
MDM 2 also binds another tumor suppressor , ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Inactivation of the ARF MDM 2 p 53 pathway in sporadic Burkitt ' s lymphoma in children . ^^^ Data derived from cell culture and animal models suggest that the inactivation of the ARF MDM 2 p 53 apoptotic signaling pathway may be a necessary secondary event for the development of BL . ^^^ We investigated the ARF MDM 2 p 53 pathway in tumor specimen from 24 children with sporadic BL / B ALL . ^^^ Our results indicate that the ARF MDM 2 p 53 apoptotic pathway is disrupted in about 55 % of the cases of childhood sporadic BL . ^^^ We suggest that in addition to the inactivation of the ARF MDM 2 p 53 protective checkpoint function other antiapoptotic mutations may occur in a substantial part of children with sporadic BL . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Unlike nucleoplasmic localized MDM 2 and p 53 , ARF localizes in the nucleolus . ^^^ The ability of ARF to block cell cycle progression through the MDM 2 p53 pathway and to suppress ribosomal biogenesis through B 23 suggest a role for ARF in coordinating inhibitions of growth and proliferation . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The interaction between p 19 ( Arf ) and NPM requires amino acid sequences at the Arf amino terminus , which are also required for Mdm 2 binding , as well as the central acidic domain of NPM and an adjacent segment that regulates NPM oligomerization . ^^^ The interaction between p 19 ( Arf ) and NPM occurs in primary mouse embryonic fibroblasts , including those lacking both Mdm 2 and p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
This process is inhibited by p 53 phosphorylation and by sequestration of Mdm 2 by ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Functional and expression analysis of Mdm 2 , MdmX , and Arf showed lack of involvement of these p 53 regulators in the observed defect of p 53 function in RCC . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The stability of p 53 protein is primarily regulated in normal non transformed cells by two interplayers : Mdm 2 and p 14 ( ARF ) . ^^^ Relocation of p 53 , Mdm 2 , and p 14 ( ARF ) to the nucleolus seems to regulate , at least partially , the steady state of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We analyzed 72 cases of meningiomas for determining the methylation status of p 14 ( ARF ) gene and the immunohistochemical expression of MDM 2 protein to explain p 53 protein expression in these meningiomas . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
METHODS : p 53 , its upstream regulators ( p 14 ( ARF ) and HDM 2 ) , and downstream effectors of the apoptotic pathway ( BAX and BCL 2 ) were studied in 118 NSCLC specimens . p 53 was analyzed by single stranded conformation polymorphism analysis covering exons 2 11 and by immunohistochemistry ( IHC ) . p 14 ( ARF ) was analyzed by methylation specific polymerase chain reaction and IHC . ^^^ RESULTS : Of 118 NSCLC specimens that were analyzed , p 53 alterations were detected in 74 tumors ( 63 % ) , p 14 ( ARF ) inactivation was detected in 53 tumors ( 45 % ) , and overexpression of HDM 2 was found in 31 tumors ( 26 % ) , including 6 tumors with gene amplification . ^^^ Greater than 90 % of the alterations were due to abnormalities of p 53 , p 14 ( ARF ) , or HDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
BACKGROUND : To clarify the roles of the p 53 MDM2 p 14 ( ARF ) cell cycle regulation system in oncogenesis and cytodifferentiation of odontogenic tumors , p 53 gene status and expression of p 53 , MDM 2 , and p 14 ( ARF ) proteins was analyzed in ameloblastomas as well as tooth germs . ^^^ METHODS : Paraffin sections of 16 tooth germs and 46 benign and 5 malignant ameloblastomas were examined immunohistochemically for the expression of p 53 , MDM 2 , and p 14 ( ARF ) proteins . ^^^ Expression of MDM 2 and p 14 ( ARF ) was detected in all samples of normal and neoplastic odontogenic epithelium , and the expression ratios in tooth germs tended to be lower than those in benign and malignant ameloblastomas . ^^^ In ameloblastomas , expression of p 53 , MDM 2 , and p 14 ( ARF ) was significantly higher in plexiform cases than in follicular cases . ^^^ Markedly decreased reactivity for p 53 , MDM 2 , and p 14 ( ARF ) was detected in keratinizing and granular cells in ameloblastoma subtypes . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
OBJECTIVE : To investigate the expression of p 14 ( ARF ) , p 53 , mdm 2 and p 21 ( WAF / CIP1 ) proteins and their relationship in exocrine pancreatic carcinoma . ^^^ METHODS : Specimens of pancreatic carcinoma , adjacent non neoplastic pancreatic tissue and pancreatic benign lesions were examined for p 14 ( ARF ) , p 53 , mdm 2 and p 21 ( WAF / CIP1 ) protein expression by tissue microarray technique and immunohistochemistry . ^^^ RESULTS : The expression of p 14 ( ARF ) , p 53 , mdm 2 and p 21 ( WAF / CIP1 ) proteins in pancreatic carcinoma were 35 . 3 % ( 59 / 167 ) , 57 . 5 % ( 96 / 101 ) , 64 . 1 % ( 107 / 167 ) and 39 . 5 % ( 66 / 167 ) respectively . ^^^ Mdm 2 protein expression correlated significantly with tumor differentiation ( P < 0 . 05 ) , while p 14 ( ARF ) protein expression correlated significantly with the age of patients and metastasis ( P < 0 . 05 ) . ^^^ CONCLUSIONS : Overexpression of p 53 and mdm 2 and loss of p 14 ( ARF ) and p 21 ( WAF / CIP1 ) expression may contribute to the pathogenesis of pancreatic carcinoma . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The tumor suppressor protein ARF ( alternate reading frame ) inhibits MDM 2 to stabilize and activate the functions of p 53 . ^^^ We show that ARF interacts with c Myc independently of MDM 2 or p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Human tumors are believed to harbor a disabled p 53 tumor suppressor pathway , either through direct mutation of the p 53 gene or through aberrant expression of proteins acting in the p 53 pathway , such as p 14 ( ARF ) or Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p 14 ( ARF ) protein , the product of an alternate reading frame of the INK4A / ARF locus on human chromosome 9p21 , disrupts the ability of MDM 2 to target p 53 for proteosomal degradation and causes an increase in steady state p 53 levels , leading to a G ( 1 ) and G ( 2 ) arrest of cells in the cell cycle . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In addition , Adp14ARF mediated expressing of p 14 ( ARF ) was associated with increased levels of p 53 , p 21 , and mdm 2 protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
We created a series of Tsg 101 conditional knock out cell lines that lack p 53 , p 21 ( Cip 1 ) , or p 19 ( Arf ) to determine the involvement of the Mdm 2 p53 circuit as a regulator for G ( 1 ) / S progression and cell death . ^^^ The Cre mediated excision of Tsg 101 in immortalized fibroblasts that lack p 19 ( Arf ) seemed not to alter the ability of Mdm 2 to sequester p 53 , and the p 21 mediated G ( 1 ) arrest was not restored . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Factors such as HAUSP , p 14 ( ARF ) , and MdmX play important regulatory roles in p 53 ubiquitination / deubiquitination and their interplay with Mdm 2 and p 53 compound layers of complexity for regulating this important pathway . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Binding of p 14 Arf to WRN is multivalent and resembles the binding of p 14 Arf to Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Oncogenes activate ARF , which interacts with and inhibits the ubiquitin ligase MDM 2 , resulting in p 53 stabilization and activation . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF impedes NPM / B23 shuttling in an Mdm 2 sensitive tumor suppressor pathway . ^^^ The Mdm 2 oncogene outcompetes NPM / B23 for ARF binding , and introduction of Mdm 2 reverses ARF ' s p 53 independent properties : in vitro , NPM is released from ARF containing protein complexes , and in vivo S phase progression ensues . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Western blot analysis revealed that whereas MDM 2 gene expression does not change , p 14 ( ARF ) , a negative protein regulator of MDM 2 , increases . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
E1A preferentially bound to Mdm 4 rather than Mdm 2 and formed a complex with p 53 in the presence of Mdm 4 , resulting in the stabilization of p 53 in a p 14 ( ARF ) independent manner . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The ARF tumor suppressor is a nucleolar protein that activates p 53 dependent checkpoints by binding Mdm 2 , a p 53 antagonist . ^^^ Despite persuasive evidence that ARF can bind and inactivate Mdm 2 in the nucleoplasm , the prevailing view is that ARF exerts its growth inhibitory activities from within the nucleolus . ^^^ Notably , ARF binds NPM through the same domains that mediate nucleolar localization and Mdm 2 binding , suggesting that NPM could control ARF localization and compete with Mdm 2 for ARF association . ^^^ Indeed , NPM knockdown markedly enhanced ARF Mdm 2 association and diminished ARF nucleolar localization . ^^^ These data suggest that NPM inhibits ARF ' s p 53 dependent activity by targeting it to nucleoli and impairing ARF Mdm 2 association . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Notably , Mdm 2 overexpression inhibited DNA double strand break repair , and this was independent of p 53 and ARF , the alternative reading frame of the Ink4alocus . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In addition to activating p 53 through binding Mdm 2 , ARF possesses other functions , including an ability to repress the transcriptional activity of the antiapoptotic RelA ( p 65 ) NF kappaB subunit . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The estrogen effects on p 53 location and transcriptional activity may involve the mdm 2 protein since both events were reversed following MCF 7 transfection with plasmid encoding the ARF cDNA . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
MdmX inhibits ARF mediated Mdm 2 sumoylation . ^^^ In this present work , we report that MdmX can undergo ARF mediated sumoylation similar to that reported for Mdm 2 . ^^^ This switch from Mdm 2 sumoylation to Mdm 2 ubiquitination may explain the destablization of Mdm 2 previously observed in cells overexpressing both ARF and MdmX . ^^^ Given that MdmX can heterodimerize with Mdm 2 and separately associate with ARF we employed a series of MdmX mutants to examine how MdmX blocks Mdm 2 sumoylation . ^^^ A MdmX miniprotein capable of binding to ARF , but not p 53 or Mdm 2 was able to competitively inhibit Mdm 2 sumoylation and reverse ARF mediated activation of p 53 transactivation . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Arf triggers sumoylation of many cellular proteins , including Mdm 2 and nucleophosmin ( NPM / B23 ) , with which p 19 ( Arf ) physically interacts in vivo , and this occurs equally well in cells expressing or lacking functional p 53 . ^^^ In an Arf null NIH 3T3 cell derivative ( MT Arf cells ) engineered to reexpress an Arf transgene driven by a zinc inducible metallothionein promoter , sumoylation of endogenous Mdm 2 and NPM proteins was initiated as p 19 ( Arf ) was induced and was observed before p 53 dependent cell cycle arrest . ^^^ Two Arf mutants , one of which binds to Mdm 2 and NPM but is excluded from nucleoli and the other of which enters nucleoli but is handicapped in binding to Mdm 2 and NPM , were defective in inducing sumoylation of these two target proteins and did not localize bulk sumoylated molecules to nucleoli . ^^^ The CELO adenovirus protein , Gam 1 , which inhibits the SUMO activating enzyme ( E 1 ) and leads to down regulation of the SUMO conjugating enzyme ( E2 / Ubc9 ) , had no overt effect on the ability of p 19 ( Arf ) to activate p 53 or the p 53 responsive genes encoding Mdm 2 and p 21 ( Cip 1 ) , despite the fact that Arf induced sumoylation of Mdm 2 was blocked . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
MDMX level is regulated by MDM 2 mediated poly ubiquitination , which results in its accelerated degradation after DNA damage or expression of ARF . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
These included three genes coding for proteins in the p 53 pathway ( TP 53 , p 14 ( ARF ) and MDM 2 ) , four in the Rb 1 pathway ( CDKN2A , CDKN2B , RB 1 and CDK 4 ) and PTEN and EGFR . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Notably , inactivation of ARF BP 1 , but not Mdm 2 , suppresses the growth of p 53 null cells in a manner reminiscent of ARF induction . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Elevated levels of p 53 after TIF IA depletion are due to increased binding of ribosomal proteins , such as L 11 , to MDM 2 and decreased interaction of MDM 2 with p 53 and p 19 ( ARF ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
PROCEDURE : Primary ependymomas at diagnosis or relapse from 24 children were analyzed for p 53 pathway , using a functional assay in yeast , RT PCR , Western blot analysis , and / or immunohistochemistry for TP 53 mutation , p 14 ( ARF ) deletion and promoter hypermethylation , MDM 2 and PAX 5 expression , respectively . p 53 mediated response to radiation induced DNA damage was evaluated using Western blot and flow cytometry analysis in two ependymoma xenograft models , IGREP 37 and IGREP 83 , derived from primary anaplastic childhood ependymomas . ^^^ RESULTS : No TP 53 , MDM 2 , p 14 ( ARF ) , PAX 5 gene abnormalities were detected in the primary ependymomas tumors and xenografts tested . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
These examples include both more recently described signaling proteins , such as p 53 , alpha synuclein , HMGA , the Rieske protein , estrogen receptor alpha , chaperones , GCN 4 , Arf , Hdm 2 , FlgM , measles virus nucleoprotein , RNase E , glycogen synthase kinase 3beta , p 21 ( Waf1 / Cip1 / Sdi1 ) , caldesmon , calmodulin , BRCA 1 and several other intriguing proteins , as well as historical prototypes for signaling , regulation , control and molecular recognition , such as the lac repressor , the voltage gated potassium channel , RNA polymerase and the S 15 peptide associating with the RNA polymerase S protein . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The tumor suppressor ARF competes with KAP 1 in MDM 2 binding ; oncogene induction of ARF expression reduces MDM 2 KAP1 interaction . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Moreover , we provide evidence that ARF inhibits the E2F activated genes independently of p 53 and Mdm 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Since p 14 ( ARF ) has been demonstrated to inhibit p 53 degradation by binding to MDM 2 , repression of p 14 ( ARF ) expression in t ( 8 ; 21 ) AML may facilitate the degradation of p 53 by MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
This is reminiscent of the c Myc > p 19 ( ARF ) mid R : Mdm 2 pathway and might function as a complementary arm to ensure the proper cellular response to oncogenic and / or apoptotic stimuli . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The downregulation of E2F1 upon MDM 2 inhibition was not due to either pRB or p 14 ( Arf ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
A novel ARF binding protein ( LZAP ) alters ARF regulation of HDM 2 . ^^^ In the present study , we show that LZAP reversed the ability of ARF to inhibit HDM 2 ' s ubiquitin ligase activity towards p 53 , but simultaneously co operated with ARF , maintaining p 53 stability and increasing p 53 transcriptional activity . ^^^ ARF binds MDM 2 ( murine double minute 2 ) and releases p 53 from inhibition by MDM 2 , resulting in stabilization , accumulation and activation of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In cultured mouse embryo fibroblasts , p 19 ( Arf ) accomplishes this independently of two established effectors Mdm 2 and p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The p 14 alternate reading frame ( ARF ) tumor suppressor plays a central role in cancer by binding to mdm 2 ( Hdm 2 in humans ) and enhancing p 53 mediated apoptosis following DNA damage and oncogene activation . ^^^ We find that DNA damage disrupts the interaction of ARF with the nucleolar protein B 23 ( nucleophosmin ) and promotes a transient p 53 independent translocation of ARF to the nucleoplasm , resulting in a masking of the ARF NH 2 terminus that correlates with the appearance of ARF Hdm 2 complexes . ^^^ Although the redistribution of ARF is independent of p 53 and likely to be regulated by interactions other than Hdm 2 , ARF does not promote UV sensitization unless p 53 is expressed . ^^^ It is unclear , however , how ARF initiates its involvement in the p53 / mdm2 pathway , as p 53 and mdm 2 are located in the nucleoplasm , whereas ARF is largely nucleolar in tumor cells . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Other p 53 related genes including p21WAF1 , p27Kip1 , MDM 2 , and the p16INK4a alternate reading frame ( ARF ) sequence showed similar patterns of differential mRNA expression . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Our aim was to determine the frequency of p 53 mutations , p 14 ( ARF ) methylation , or deletion and MDM 2 amplification in 23 neuroblastoma cell lines ( 6 derived at diagnosis and 17 derived at relapse ) . ^^^ Two cell lines were methylated for p 14 ( ARF ) ( GIMEN and PER 108 ) , one of which had low levels of p 14 ( ARF ) mRNA expression which increased following demethylation with 5 aza 2 / deoxycytidine treatment ( GIMEN ) , and four cell lines were confirmed to be MDM 2 amplified . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Decreased Mdm 2 expression inhibits tumor development induced by loss of ARF . ^^^ The tumor suppressor p14 / p19 ( ARF ) regulates Mdm 2 , which is known for controlling the p 53 tumor suppressor . ^^^ Here we report that loss of one allele of Mdm 2 in cells that lack ARF resulted in a decreased rate of proliferation , fewer chromosomal aberrations , and suppression of Ras induced transformation . ^^^ Moreover , a haploinsufficiency of Mdm 2 inhibited spontaneous tumor development in ARF null mice . ^^^ Remarkably , Mdm 2 ( + / ) ARF ( / ) mice survived an average of 6 months longer than Mdm 2 ( + / + ) ARF ( / ) mice . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF encodes a potent tumor suppressor that antagonizes MDM 2 , a negative regulator of p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF is upregulated by oncogenic stimuli and is a critical regulator of p 53 stability through interactions with the mdm 2 and ARF BP1 / Mule ubiquitin ligases . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
ARF can activate p 53 through nucleolar sequestration of Mdm 2 . ^^^ Finally , the ability of p33ING1 to cause cell cycle arrest and induction of p21CIP1 , or Mdm 2 , is impaired in ARF deficient primary mouse fibroblasts . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Notably , MDM 2 downregulated the protein level of TCAP through the proteasomal pathway , and this downregulation was inhibited by p 14 ( ARF ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Could this account for the Mdm 2 and p 53 independent tumor suppressive effects of ARF ? . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Taken together , our data demonstrate that the response of p 53 null cells to ARF is cell type dependent and involves factors other than Mdm 2 and E2F1 . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
On incubation with CDDP , levels of positively regulated p 53 transcriptional targets p 21 ( WAF ) , PIG 3 , MDM 2 , Bax , and PUMA increased in p 14 ( ARF ) deficient cells , whereas negatively regulated survivin decreased . ^^^ Significantly , p 53 induced apoptosis was activated by CDDP in p 14 ( ARF ) deficient cells , and treatment with p 53 specific siRNA rendered them more CDDP resistant . p 53 was also activated by : 1 ) inhibition of MDM 2 ( using nutlin 3 ) ; 2 ) transient overexpression of p 14 ( ARF ) ; and 3 ) targeting of survivin using antisense oligonucleotides . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
By functioning specifically to oppose abnormally prolonged and sustained proliferative signals produced by activated oncogenes , the ARF tumour suppressor antagonizes functions of MDM 2 to induce protective responses that depend on the p 53 transcription factor and its many target genes . ^^^ However , ARF has been reported to physically associate with proteins other than MDM 2 and to have p 53 independent activities , most of which remain controversial and poorly understood . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
These alterations include deletions of negative regulatory elements ( TP 53 , CDKN 2 , MTS 2 ) and amplification of positive factors ( MDM 2 , CDK 4 ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
These alterations lead to changes in the expression of several genes ; protein 53 ( p 53 ) , retinoblastoma ( RB ) , interferon ( INF ) alpha / beta , cyclic AMP dependent kinase number 2 ( CDKN 2 ) , mutated in multiple advanced cancers 1 ( MMAC 1 ) , deleted in colon carcinoma ( DCC ) , epidermal growth factor receptor ( EGFR ) , platelet derived growth factor ( PDGF ) , platelet derived growth factor receptor ( PDGFR ) , MDM 2 , GL 1 , CDK 4 and SAS during the genesis and progression of human gliomas . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Twenty primary central nervous system lymphomas ( PCNSL ) from immunocompetent patients ( nineteen B cell lymphomas and one T cell lymphoma ) were investigated for genetic alterations and / or expression of the genes BCL 2 , CCND 1 , CDK 4 , CDKN1A , CDKN2A , MDM 2 , MYC , RB 1 , REL , and TP 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Mutations of TP 53 , amplification of EGFR , MDM 2 and CDK 4 , and deletions of CDKN2A in malignant astrocytomas . ^^^ The genetic alterations analyzed were : deletion of CDKN2a / p16 gene , TP 53 mutations , and amplification of EGFR , MDM 2 and CDK 4 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In total , 11 / 12 MPNSTs showed DNA changes in one or more of the genes CDKN2A , CDKN2B , RB 1 , CDK 4 , MDM 2 , and CCND 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
More focussed molecular genetic analyses revealed neither aberrations of the TP 53 and CDKN2A tumor suppressor genes nor amplification of the EGFR , CDK 4 , and MDM 2 proto oncogenes . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
The scarcity of such cases generally requires that molecular analyses of PMAs are based on the utilization of paraffin embedded material , and here we have used 39 such specimens to examine the incidence and prognostic significance of oncogene and tumor suppressor gene alterations ( including amplifications of EGFR , CDK 4 , and MDM 2 as well as inactivating mutations of CDKN2A , TP 53 , and PTEN ) in these tumors . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Therefore , we compared 2 age and gender matched groups of GBM patients with different post operative time to tumor progression ( TTP ) , defined as ' short term ' for TTP of less than 6 months ( n = 21 ) , and ' long term ' for TTP of more than 24 months ( n = 21 ) for genetic alterations of the PTEN , CDKN2A and TP 53 genes as well as overexpression of the EGFR , p 53 and Mdm 2 proteins . ^^^ For the GBMs with ' short term ' TTP vs . ' long term ' TTP , the studies revealed PTEN mutations in 4 / 21 vs . 2 / 21 , TP 53 mutations in 5 / 21 vs . 8 / 21 , homozygous deletion of the CDKN2A gene in 5 / 21 vs . 6 / 21 , overexpression of EGFR in 7 / 20 vs . 10 / 20 , accumulation of p 53 protein in 9 / 20 vs . 7 / 20 and of Mdm 2 protein in 0 / 20 vs . 1 / 20 cases studied . ^^^ Taken together , our data indicate that mutations of the PTEN and TP 53 tumor suppressor genes , homozygous deletion of the CDKN2A gene as well as overexpression of the EGFR , p 53 and Mdm 2 proteins lack prognostic significance for overall survival time in patients with GBMs . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Primary glioblastomas develop in older patients and typically show EGFR overexpression , PTEN ( MMAC 1 ) mutations , CDKN2A ( p 16 ) deletions , and less frequently , MDM 2 amplification . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Molecular genetic analysis of one tumor revealed no TP 53 mutation ( exons 4 10 ) , no loss of CDKN2A , and no amplification of EGFR , CDK 4 or MDM 2 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Not only do Li Fraumeni patients develop second primary malignancies , but defects of the p 53 pathway ( p 53 mutation , MDM 2 over expression , CDKN2A deletion ) appear to be a ubiquitous feature of sporadic oral cancer as it occurs in the West . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Molecular genetic analysis of the TP 53 , PTEN , CDKN2A , EGFR , CDK 4 and MDM 2 tumour associated genes in supratentorial primitive neuroectodermal tumours and glioblastomas of childhood . ^^^ To identify molecular genetic markers that may distinguish sPNET and GBM , we investigated 12 cerebral sPNETs and six GBMs from paediatric patients for genetic alterations of the TP 53 , PTEN , CDKN2A , EGFR , CDK 4 and MDM 2 genes , as well as for allelic loss on chromosome arms 10q and 17p . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Amplification of CDK 4 or MDM 2 or homozygous deletion of CDKN2A was not detected . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Our data contain several lines of evidence supporting roles of CDKN2A and MDM 2 in progression of neoplastic disease . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
Selected SNPs belong to the following genes : ADH1B , ALDH 2 , APEX , CDKN2A , COMT , CYP1A1 , CYP1A2 , CYP1B1 , CYP2A6 , CYP2C19 , CYP2C9 , CYP2E1 , CYP3A4 , DRD 2 , DRD 4 , EPHX 1 , ERCC 1 , ERCC 2 , ERCC 4 , ERCC 5 , GRPR , GSTA 4 , GSTM 3 , GSTP 1 , GSTT 2 , LIG 3 , MDM 2 , MGMT , MPO , NAT 1 , NAT 2 , NQO 1 , OGG 1 , PCNA , POLB , SLC6A3 , SOD 2 , TP 53 , XRCC 1 , XRCC 2 , XRCC 3 , and XRCC 9 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
TP 53 , MDM 2 and CDKN2A / p14ARF genes were unchanged . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
METHODS : A search for loss of heterozygosity ( LOH ) on chromosome 1p , 9p , 10q , 19q , EGFR ( epidermal growth factor receptor ) , CDK 4 , and MDM 2 ( mouse double minute ) amplifications , CDKN2A ( INK4A / ARF ) homozygous deletions , p 53 expression , was performed in a series of 220 primary glioblastomas . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
A modulation of the p 53 target gene ( p21 / WAF , bax , mdm 2 , and thrombospondin 1 ) expression was observed upon Mts 1 induction in the cells expressing the wild type p 53 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In order to understand better the possible role of cell cycle regulating molecules in the pathogenesis of Hodgkin ' s disease ( HD ) , the immunohistochemical distribution pattern of p16INK4A was investigated and compared with pRb , p 53 , and MDM 2 protein status in 44 HD cases . ^^^ A significant correlation was observed between immunoreactivity of p16INK4A and MDM 2 and the number of HRS cells ( P = . 0012 and P = . 018 , respectively ) . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
INK4a is a prognostic marker in resected ductal pancreatic cancer : an analysis of p16INK4a , p 53 , MDM 2 , an Rb . ^^^ OBJECTIVE : To identify the prognostic relevance of the G1 / S cell cycle regulator genes p16INK4a , p 53 , MDM 2 , and Rb in patients with resected ductal pancreatic cancer ( PC ) . ^^^ Protein expression of p 16 , p 53 , MDM 2 , and Rb was investigated , and mutation analysis of p16INK4a and p 53 was performed . p16INK4a promoter hypermethylation was examined by methylation specific polymerase chain reaction . ^^^ CONCLUSIONS : The presence of p16INK4a alterations in resected tumors of patients with PC is connected with a worse prognosis , indicating patients that might benefit from adjuvant therapy regimens . p 53 alterations , MDM 2 overexpression , and loss of Rb expression could not be identified as prognostic markers from this study , but a larger study with greater statistical power might show a different result with regard to p53 . . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
RESULTS : All of the other proteins differed from normal IHC profiles in both groups that showed significant higher proliferating rates , decreases in p27KIP1 , pRb , and cyclin D 1 , as well as increases in p16INK4A , p 53 , MDM 2 , and p21WAF1 levels , in comparison with normal PT glands , with the exception of cyclin D 3 . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
In this study , 98 foci of IPNL identified in 39 surgically resected hepatolithiatic livers were investigated for expression of p16INK4a , cyclin D 1 , p21WAF1 / CIP1 , p 53 , mouse double minute 2 ( MDM 2 ) , and pRb . ^^^
Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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Interacting proteins: Q8N726 and Q00987	Pubmed	SVM Score :0.0
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