| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.80722541 |
| MDM 2 interacts with MDMX through their RING finger domains . 0.80722541^^^ Interaction of MDMX with MDM 2 through the C terminal RING finger domains resulted in inhibiting degradation of MDM 2 . 0.51191807^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.72524196 |
| 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 . 0.72524196^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Stabilization of the MDM 2 oncoprotein by interaction with the structurally related MDMX protein . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Using a series of MdmX deletions , we have determined that there are two distinct domains of the MdmX protein that can stabilize p 53 in the presence of Mdm 2 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The Mdmx protein , structurally homologous to Mdm 2 , does not target p 53 for degradation , but even stabilizes both p 53 and Mdm 2 , an activity most likely mediated by heterodimerization of the RING fingers of Mdm 2 and Mdmx . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| This truncated MDMX protein , termed MDMX S , represents only the p 53 binding domain and binds and inactivates p 53 better than full length MDMX or MDM 2 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| In contrast , the Mdmx protein , although structurally similar to Mdm 2 , can not ubiquitylate or degrade p 53 in vivo . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Little is known about the regulation of Hdmx expression levels , apart from the observation that the Mdmx protein can be cleaved by caspase 3 in a p 53 inducible manner . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDMX : a novel p 53 binding protein with some functional properties of MDM 2 . ^^^ This new protein has been called MDMX on the basis of its structural similarity to MDM 2 , which is especially notable in the p 53 binding domain . ^^^ In addition , the putative metal binding domains in the C terminal part of MDM 2 are completely conserved in MDMX . ^^^ The middle part of the MDMX and MDM 2 proteins shows a low degree of conservation . ^^^ Northern blotting showed that MDMX , like MDM 2 , is expressed in all tissues tested , and that several mRNAs for MDMX can be detected . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| We recently reported the identification of a mouse cDNA encoding a new p 53 associating protein that we called Mdmx because of its structural similarity to Mdm 2 , a well known p 53 binding protein . ^^^ The homology between Mdmx and Mdm 2 is most prominent in the p 53 binding domain and the putative metal binding domains . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The expression of other oncogenes , which have previously found to be activated in combination with pim 1 in lymphomagenesis , such as gfi 1 / pal 1 , frat 1 and tiam 1 , and also of the mdm 2 and mdm 10 oncogenes , appeared not to be affected . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mdm 2 and MDMX are two structurally related p 53 binding proteins which show the highest level of sequence similarity in the N terminal p 53 binding domains . ^^^ Apart from its ability to inhibit p 53 mediated transcription , a feature it shares with mdm 2 , very little is known about the physiological functions of MDMX . ^^^ We present data on the structural similarity between the p 53 binding pockets of mdm 2 and MDMX using p 53 and phage selected peptides . ^^^ From the results we conclude that our recently devised innovative approach to reverse the mdm 2 mediated inhibition of p 53 ' s transactivation function in vivo would probably target MDMX as well . ^^^ Strategies for selectively targeting mdm 2 and MDMX are suggested and a possible mechanism for regulating the p 53 mdm2 / MDMX interactions by protein phosphorylation is discussed . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The MDMX gene product is related to the MDM 2 oncoprotein , both of which interact with the p 53 tumor suppressor . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDM 2 and MDMX bind and stabilize the p 53 related protein p 73 . ^^^ Like MDM 2 , the MDM 2 related protein MDMX also bound p 73 and stabilized the level of p 73 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The mdmx gene was shown to possess high homology to the mdm 2 gene and to encode a protein that can bind p 53 and block p 53 transactivation . ^^^ Because Mdm 2 protein blocks the growth suppressive activity of the p 53 tumor suppressor protein through similar activities , we examined the expression patterns of mdmx to determine how MdmX expression correlates with p 53 protein levels . ^^^ Like mdm 2 , mdmx gene expression was constitutive during serum deprivation / restimulation of murine fibroblasts and differentiation of either murine teratocarcinoma or preadipocyte cells . ^^^ In contrast , whereas mdm 2 gene expression was induced after cisplatin damage to ovarian carcinoma cells , mdmx expression remained constitutive . ^^^ Because p 53 transactivation is critical following a genotoxic stress , we examined p 53 : MdmX complexes after in vitro DNA PK phosphorylation , a posttranslational modification that blocks p 53 association with Mdm 2 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDM 2 and MDMX inhibit the transcriptional activity of ectopically expressed SMAD proteins . ^^^ Here we show that MDM 2 and the structurally related protein MDMX can inhibit the transcriptional activity of ectopically expressed SMAD 1 , SMAD 2 , SMAD 3 , and SMAD 4 . ^^^ When SMAD 4 was coexpressed with either MDM 2 or MDMX , nuclear accumulation of SMAD 4 was strikingly inhibited . ^^^ We have no evidence that SMAD 4 binds directly to MDM 2 or MDMX ; hence , the inactivation and nuclear exclusion of SMAD 4 by MDM2 / MDMX may involve other indirect mechanisms . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Amplification and overexpression of the MDM 4 ( MDMX ) gene from 1q32 in a subset of malignant gliomas without TP 53 mutation or MDM 2 amplification . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| In this review , we present evidence for the existence of three highly conserved regions ( CRs ) shared by MDM 2 proteins and MDMX proteins of different species . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Indeed , like p 53 , p 73 as well ( 1 ) can bind mdmX , mdm 2 , p300 / CAF and adenovirus E 4 orf6 proteins , ( 2 ) can trigger several promoters including p 21 , bax , mdm 2 , gadd 45 , cyclin G , IGFBP 3 , 14 3 3 sigma , ( 3 ) is able to trigger cell death , ( 4 ) is involved in the DNA damage response , although through a different pathway . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDM 2 and MDMX can interact differently with ARF and members of the p 53 family . ^^^ Little is known about the interaction and selectivity of different members of the p 53 family ( p 53 , p 63 , and p 73 ) and the MDM 2 family ( MDM 2 and MDMX ) . ^^^ Here we show that the transcriptional activities of p 53 and p 73 , but not that of p 63 , were inhibited by both MDM 2 and MDMX . ^^^ Moreover , ectopically expressed MDM 2 and MDMX could induce alterations in the subcellular localization of p 73 , but did not affect the subcellular localization of p 53 and p 63 . ^^^ 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 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The mdmx gene is the first additional member of the mdm 2 gene family to be isolated . ^^^ The genomic organization of the mdmx gene is identical to that of mdm 2 except at the 5 ' end of the gene near the p 53 responsive element . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The recently discovered MDM 2 related protein MDM 4 ( also known as MDMX ) has some of the same properties as MDM 2 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Using a yeast two hybrid screen we have identified the MDM 2 related protein , MDMX , as an E2F 1 binding protein . ^^^ We also find that this transcriptionally inactive E2F 1 mutant is capable of degrading the MDMX related protein MDM 2 and the MDMX isoform MDMX S . ^^^ Mapping of the E2F 1 C terminus reveals that neither a previously characterized C terminal MDM 2 binding domain nor the pRb binding domain on E2F 1 is required for MDMX and MDM 2 degradation . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Two gene families , the p 53 family ( p 53 , p 63 and p 73 ) and the Mdm 2 family ( Mdm 2 and MdmX ) , serve as major integrators of the signals generated by genotoxic and oncogenic stress . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDMX is a p 53 binding protein , which shares a high degree of homology with MDM 2 , a negative regulator of the tumor suppressor p 53 . ^^^ MDMX has been shown to counteract MDM 2 dependent p 53 degradation and to stabilize p 53 in its inactive form . ^^^ In conclusion , our results demonstrate that , in analogy to MDM 2 , MDMX may be subjected to proteolytic modifications that regulate its intracellular levels . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mutual dependence of MDM 2 and MDMX in their functional inactivation of p 53 . ^^^ MDMX , an MDM 2 related protein , has emerged as yet another essential negative regulator of p 53 tumor suppressor , since loss of MDMX expression results in p 53 dependent embryonic lethality in mice . ^^^ In addition , results of biochemical studies have suggested that MDMX inhibits MDM 2 mediated p 53 degradation , thus contradicting its role as defined in gene knockout experiments . ^^^ Using cells deficient in either MDM 2 or MDMX , we demonstrated that these two p 53 inhibitors are in fact functionally dependent on each other . ^^^ In the absence of MDMX , MDM 2 is largely ineffective in down regulating p 53 because of its extremely short half life . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDMX is an MDM 2 like protein that shares with MDM 2 the ability to interact with p 53 and , in turn , inhibit p 53 mediated transcription . ^^^ Our results indicate that MDMX shares with MDM 2 the ability to regulate a potentially important post translational modification of p 53 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The MDM 2 homolog MDMX is an important regulator of p 53 activity during embryonic development . ^^^ Coexpression of MDM 2 or p 53 is sufficient to induce MDMX nuclear translocation , suggesting that activation of p 53 and induction of MDM 2 expression can contribute to this process . ^^^ Stable transfection of MDMX into U2OS cells does not alter p 53 level but results in reduced p 53 DNA binding activity and reduced MDM 2 expression . ^^^ 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: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm 2 ubiquitination . ^^^ It has been well documented that Mdm 2 and its homologue MdmX not only are critical negative regulators of the tumor suppressor p 53 but that both Mdm 2 and MdmX interact to affect the function of the other . ^^^ Although Mdm 2 has been established as a RING finger ubiquitin ligase , MdmX has not been shown to possess this activity despite the extensive sequence homology between their respective RING finger domains . ^^^ The addition of Mdm 2 to in vitro ubiquitination assays containing MdmX results in a synergistic increase of ubiquitin conjugation . ^^^ This study also suggests that ubiquitination of Mdm 2 and MdmX may not serve as a signal for degradation , as we show that each are capable of synthesizing non lysine 48 polyubiquitin chains and , in fact , utilize multiple lysine linkages . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Our goal in this study was to examine whether overexpression of Mdm 2 or MdmX , a Mdm 2 related protein , could affect Smad induced transactivation . ^^^ As downstream signaling elements of the TGF beta pathway , Smads represent one potential target for Mdm 2 and MdmX . ^^^ Here we show that MdmX but not Mdm 2 is capable of inhibiting Smad induced transactivation . ^^^ Based on deletion mutant analysis , MdmX inhibition of Smad transactivation was independent of the p 53 and Mdm 2 interaction domains , yet required amino acid residues 128 444 . ^^^ Additionally , mouse embryo fibroblasts ( MEFs ) lacking p 53 and MdmX showed enhanced Smad transactivation when compared to MEFs lacking either p 53 or p 53 and Mdm 2 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Overexpression of Mdm 2 and MdmX fusion proteins alters p 53 mediated transactivation , ubiquitination , and degradation . ^^^ Mdm 2 and MdmX function as cellular regulators of the p 53 tumor suppressor protein . ^^^ MdmX , a p 53 binding protein sharing a high degree of structural homology with Mdm 2 , has emerged as another negative regulator of the p 53 tumor suppressor . ^^^ MdmX has also been shown to block p 53 transactivation but unlike Mdm 2 can not induce p 53 degradation . ^^^ Since MdmX also possesses a ring finger domain that allows MdmX to associate with Mdm 2 , this study focused on elucidating how the ring and zinc fingers of these two proteins affected p 53 function . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| To test this possibility , we generated a series of MDM2 / MDMX chimeric proteins to assess the contribution of each domain of MDM 2 to the ubiquitination process . ^^^ MDMX is a close structural homolog of MDM 2 that nevertheless lacks the E 3 ligase activity in vivo . ^^^ We demonstrate here that MDMX gains self ubiquitination activity and becomes extremely unstable upon introduction of the MDM 2 RFD , indicating that the RFD is essential for self ubiquitination . ^^^ This MDMX chimeric protein , however , is unable to ubiquitinate p 53 in vivo despite its E 3 ligase activity and binding to p 53 , separating the self ubiquitination activity of MDM 2 from its ability to ubiquitinate p 53 . ^^^ Significantly , fusion of the central acidic domain ( AD ) of MDM 2 to the MDMX chimeric protein renders the protein fully capable of ubiquitinating p 53 , and p 53 ubiquitination is associated with p 53 degradation and nuclear export . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDM 2 promotes ubiquitination and degradation of MDMX . ^^^ Recent studies showed that the MDM 2 homolog MDMX is also an important regulator of p 53 . ^^^ We present evidence that MDM 2 promotes MDMX ubiquitination and degradation by the proteasomes . ^^^ Promotion of MDM 2 mediated MDMX ubiquitination requires the N terminal domain of ARF , which normally inhibits MDM 2 ubiquitination of p 53 . ^^^ An intact RING domain of MDM 2 is also required , both to interact with MDMX and to provide E 3 ligase function . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| DNA damage induced MDMX degradation is mediated by MDM 2 . ^^^ We also demonstrate that DNA damage induced MDMX reduction is mediated by MDM 2 , which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p 53 activation . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mdm 4 ( MdmX ) is a p 53 binding protein that shares structural similarities with Mdm 2 and has been proposed to be a negative regulator of p 53 function . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Based on knockout mouse studies , Mdm 2 and MdmX have been identified as critical regulators of the p 53 tumor suppressor protein , at least during early development . ^^^ While many of the functions attributed to Mdm 2 and MdmX involve p 53 and overexpression of each gene appears to have oncogenic activities , a number of studies have suggested that each protein also possesses p 53 independent functions . ^^^ While examining the effect of Mdm 2 overexpression on E2F1 transactivation we uncovered a novel MdmX function , the ability to inhibit E2F1 transactivation in a p 53 and Mdm 2 independent manner . ^^^ |
|
| Interacting proteins: O15151 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: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| This regulation of p 53 is modulated by the Mdm 2 homologue , Mdmx . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Furthermore , the human Mdmx ortholog , Hdmx , was found to be overexpressed in a significant percentage of various human tumors and amplified in 5 % of primary breast tumors , all of which retained wild type p 53 . ^^^ |
|
| Interacting proteins: O15151 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: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mdmx and Mdm 2 : brothers in arms . ^^^ Recently , however , the Mdm 2 related protein Mdmx is taking the stage in the p 53 Mdm2 Mdmx play . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDM 2 destabilization is controlled by DNA damage activated post translational modifications and by its own RING domain , implying a possible role for the RING domain interacting protein , MDMX , in regulating MDM 2 stability . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Phosphorylation of MdmX by CDK2 / Cdc2 ( p 34 ) is required for nuclear export of Mdm 2 . ^^^ Mdm 2 and MdmX function as cellular regulators of the p 53 tumor suppressor protein . ^^^ Intriguingly , the activities of these proteins are interdependent ; MdmX stabilizes Mdm 2 , enabling its activities towards p 53 , but it also requires Mdm 2 for its nuclear localization . ^^^ Here we demonstrate that via its phosphorylation by CDK2 / Cdc2p34 , MdmX regulates nuclear export of Mdm 2 . ^^^ Consequently , cells that express MdmX ( S96A ) retain Mdm 2 in their nuclei , suggesting that export of Mdm 2 to the cytoplasm is MdmX dependent . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mdm 2 and mdmX prevent ASPP 1 and ASPP 2 from stimulating p 53 without targeting p 53 for degradation . ^^^ Mdm 2 and mdmx prevent ASPP 1 and ASPP 2 from stimulating the apoptotic function of p 53 by binding and inhibiting the transcriptional activity of p 53 . ^^^ Importantly , mdm 2 and mdmx can prevent the stimulatory effects of ASPP 1 and ASPP 2 without targeting p 53 for degradation . ^^^ These data provide a novel mechanism by which mdm 2 and mdmx act as potent inhibitors of p53 . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The activation and stabilization of the p 53 protein play a major role in the DNA damage response and are mediated by ATM dependent posttranslational modifications of p 53 and Mdm 2 , a ubiquitin ligase of p 53 . p 53 ' s response to DNA damage also depends on Mdm 2 dependent proteolysis of Mdmx , a homologue of Mdm 2 that represses p 53 ' s transactivation function . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Almost 10 years ago , a search for new p 53 interactors revealed the existence of an Mdm 2 structurally related protein , Mdmx ( or Mdm 4 ) . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDMX is a homolog of MDM 2 and is critical for regulating p 53 function during mouse development . ^^^ MDMX level is regulated by MDM 2 mediated poly ubiquitination , which results in its accelerated degradation after DNA damage or expression of ARF . ^^^ Experiments using the sumoylation deficient MDMX mutant showed that it undergoes normal ubiquitination and degradation by MDM 2 , normal nuclear translocation and degradation after DNA damage , and inhibits p 53 with wild type efficiency . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDMX is a homolog of MDM 2 that is critical for regulating p 53 function during mouse development . ^^^ MDMX degradation is regulated by MDM 2 mediated ubiquitination . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Likewise , inhibition of GSK 3 did not alter localization of p 53 and Mdm 2 or the interaction of Mdm 2 and MdmX . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Under normal circumstances Mdmx and Mdm 2 control the activity of p 53 . ^^^ Both proteins inhibit the transcriptional regulation by p 53 , while Mdm 2 also functions as an E 3 ubiquitin ligase to target both p 53 and Mdmx for proteasomal degradation . ^^^ Subsequently , HAUSP was shown to deubiquitinate Mdm 2 and Mdmx , thereby stabilizing these proteins . ^^^ ATM fine tunes p 53 ' s response to DNA damage by directly phosphorylating it , by regulating additional post translational modifications of this protein , and by affecting two p 53 regulators : Mdm 2 and Mdmx . ^^^ ATM directly and indirectly induces Mdm 2 and Mdmx phosphorylation , resulting in decreased activity and stability of these proteins . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Recently , an E2F1 mutant lacking the DNA binding domain , E2F1 ( 180 437 ) , has been implicated in degradation of MDMX and MDM 2 proteins via lysosomal proteases . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| MDM 2 and MDMX are important p 53 regulators and logical targets for stress signals . ^^^ Phosphorylated MDMX is selectively bound and degraded by MDM 2 preceding p 53 accumulation and activation . ^^^ Mutation of MDMX on S 342 , S 367 , and S 403 each confers partial resistance to MDM 2 mediated ubiquitination and degradation . ^^^ Chk 2 also stimulates MDMX ubiquitination and degradation by MDM 2 . ^^^ Therefore , the E 3 ligase activity of MDM 2 is redirected to MDMX after DNA damage and contributes to p 53 activation . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| DNA damage induced phosphorylation of MdmX at serine 367 activates p 53 by targeting MdmX for Mdm 2 dependent degradation . ^^^ Genetic data indicate that Mdmx as well as Mdm 2 plays a major role in maintaining p 53 activity at low levels in nonstressed cells . ^^^ Transfection assays indicated that the S367A mutation , in cooperation with Mdm 2 , enhances the ability of Mdmx to repress the transcriptional activity of p 53 . ^^^ The S367A mutant is more resistant to Mdm 2 dependent ubiquitination and degradation than wild type Mdmx , and Mdmx phosphorylated at S 367 is preferentially degraded by Mdm 2 . ^^^ We propose that Mdmx phosphorylation at S 367 plays an important role in p 53 activation after DNA damage by triggering Mdm 2 dependent degradation of Mdmx . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Effects of MdmX on Mdm 2 mediated downregulation of pRB . ^^^ In the present study , we assessed the effects of MdmX , a structural homolog of Mdm 2 , on the Mdm 2 mediated ubiquitination of pRB . ^^^ MdmX is known to negatively regulate p 53 function by enhancing the Mdm 2 mediated ubiquitination and degradation of p 53 . ^^^ Interestingly , MdmX inhibited the Mdm 2 mediated pRB ubiquitination . ^^^ Therefore , MdmX may have different roles in the regulation of Mdm 2 activity for ubiquitination of pRB and p53 . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The MDM 2 homolog MDMX is an important regulator of p 53 during mouse embryonic development . ^^^ DNA damage promotes MDMX phosphorylation , nuclear translocation , and degradation by MDM 2 . ^^^ Chk 2 mediated phosphorylation of MDMX on S 367 is important for stimulating 14 3 3 binding , MDMX nuclear import by a cryptic nuclear import signal , and degradation by MDM 2 . ^^^ Mutation of MDMX S 367 inhibits ubiquitination and degradation by MDM 2 , and prevents MDMX nuclear import . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| It has been shown that MDMX inhibits the activity of the tumor suppressor p 53 by primarily cooperating with the p 53 feedback regulator MDM 2 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Herein , we deal with the post translational regulation of p 53 via its specific ubiquitinating enzymes ( Mdm 2 , Mdmx , COP 1 , Pirh 2 , ARF BP1 / Mule , and CHIP ) and a deubiquitinating enzyme , herpesvirus associated ubiquitin specific protease ( HAUSP ) . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| The mechanisms by which Mdm 2 and Mdm 4 ( MdmX ) regulate p 53 remain controversial . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Moreover , no changes in total cellular p 53 , Mdm 2 , and c Abl or nuclear Mdmx were observed among the treatment groups . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mdm 2 and Mdm 4 possess nearly identical p 53 binding domains but different lids suggesting that lid modifications may select for p 53 binding . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Loss of either of the p 53 inhibitors mdm 2 or mdm 4 gives rise to a p 53 dependent embryonic lethal phenotype . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| On the other hand , MDM 4 overexpression has been reported to stabilize p 53 levels and to counteract MDM 2 degradative activity . ^^^ They also indicate a major distinction between the biological consequences of MDM 4 and MDM 2 overexpression . . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Switching mechanisms of cell death in mdm 2 and mdm 4 null mice by deletion of p 53 downstream targets . ^^^ Deletion of either mdm 2 or mdm 4 genes , which encode p 53 inhibitors , results in embryonic lethality . ^^^ The lethal phenotypes are rescued in the absence of p 53 , which indicates that increased activity of p 53 is the cause of lethality in the mdm 2 and mdm 4 null embryos . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mutation at p 53 serine 389 does not rescue the embryonic lethality in mdm 2 or mdm 4 null mice . ^^^ Mdm 2 and its homolog Mdm 4 inhibit the function of the tumor suppressor p 53 . ^^^ Targeted disruption of either mdm 2 or mdm 4 genes in mice results in embryonic lethality that is completely rescued by concomitant deletion of p 53 , suggesting that deletion of negative regulators of p 53 results in a constitutively active p 53 . ^^^ To examine the in vivo significance of serine 389 phosphorylation during embryogenesis , we crossed these mutant mice to mice lacking mdm 2 or mdm 4 . ^^^ The p53S389A allele did not alter the embryonic lethality of mdm 2 or mdm 4 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| To identify potential E1A binding proteins involved in E1A ' s anticancer activities , we screened a yeast two hybrid library and identified Mdm 4 , an Mdm 2 related p 53 binding protein , as a novel E1A binding protein . ^^^ 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 . ^^^ Although it had no effect on the p 53 Mdm2 interaction , E1A facilitated Mdm 4 binding to p 53 and inhibited Mdm 2 binding to Mdm 4 , resulting in decreased nuclear exportation of p 53 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| We studied this mechanism in 8 genes ( cyclin dependent kinase 4 [ CDK 4 ] , MDM 2 , MDM 4 , renin angiotensin system 1 , ELF 3 , GAC 1 , human epidermal growth factor receptor 2 , and platelet derived growth factor receptor A gene ) in a series of 40 oligodendrogliomas ( World Health Organization ( WHO ) grade 2 , 21 ; WHO grade 3 , 13 ; and WHO grade 2 3 oligoastrocytomas , 6 ) using real time quantitative polymerase chain reaction . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Significance of HDMX S ( or MDM 4 ) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis . ^^^ The product of the HDMX ( or MDM 4 ) gene is structurally related to the MDM 2 oncoprotein and is also capable of interacting with the tumor suppressor protein p 53 . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Rescue of Mdm 4 deficient mice by Mdm 2 reveals functional overlap of Mdm 2 and Mdm 4 in development . ^^^ The Mdm 2 and Mdm 4 genes are amplified and overexpressed in a variety of human cancers and encode structurally related oncoproteins that bind to the p 53 tumor suppressor protein and inhibit p 53 activity . ^^^ Mice deleted for either Mdm 2 or Mdm 4 die during embryogenesis , and the developmental lethality of either mouse model can be rescued by concomitant deletion of p 53 . ^^^ However , the phenotypes of Mdm 2 and Mdm 4 deficient mice suggest that Mdm 2 and Mdm 4 play nonoverlapping roles in regulating p 53 activity during development , with Mdm 2 regulating p 53 mediated cell death and Mdm 4 regulating p 53 mediated inhibition of cell growth . ^^^ Here , we describe complete rescue of Mdm 4 deficient mice by expression of an Mdm 2 transgene , and demonstrate that Mdm 2 can regulate both p 53 mediated apoptosis and inhibition of cell growth in the absence of Mdm 4 in primary cells . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| We have studied gene amplification of genes located in 1q32 ( GAC 1 , ELF 3 , MDM 4 , and ren 1 ) , 4q11 ( PDGFR alpha ) , and in 12q13 14 ( MDM 2 and CDK 4 ) using quantitative real time PCR in a group of 86 tumors consisting of 44 WHO grade 4 glioblastomas ( GBM ) ( 34 primary and 10 secondary tumors ) , 21 WHO grade 3 anaplastic astrocytomas ( AA ) , and 21 WHO grade 2 astrocytomas ( AII ) . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Tissue specific differences of p 53 inhibition by Mdm 2 and Mdm 4 . ^^^ Mdm 2 and its homolog , Mdm 4 , are critical inhibitors of p 53 that are often overexpressed in human tumors . ^^^ In mice , loss of Mdm 2 or Mdm 4 leads to embryonic lethal phenotypes that are completely rescued by concomitant loss of p 53 . ^^^ To examine the role of Mdm 2 and Mdm 4 in a temporal and tissue specific manner and to determine the relationships of these inhibitors to each other , we generated conditional alleles . ^^^ We deleted Mdm 2 and Mdm 4 in cardiomyocytes , since proliferation and apoptosis are important processes in heart development . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Synergistic roles of Mdm 2 and Mdm 4 for p 53 inhibition in central nervous system development . ^^^ Loss of Mdm 2 or Mdm 4 leads to embryo lethal phenotypes that are p 53 dependent . ^^^ To determine whether Mdm 2 and Mdm 4 inhibit p 53 function redundantly in a more restricted cell type , conditional alleles were crossed to a neuronal specific Cre transgene to delete Mdm 2 and Mdm 4 in the CNS . ^^^ Mice lacking Mdm 2 in the CNS developed hydranencephaly at embryonic day 12 . 5 due to apoptosis , whereas Mdm 4 deletion showed a proencephaly phenotype at embryonic day 17 . 5 because of cell cycle arrest and apoptosis . ^^^ Additionally , Mdm 2 and Mdm 4 had a gene dosage effect , because loss of three of the four Mdm alleles also showed a more accelerated CNS phenotype than deletion of either gene alone . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| Mdm 4 and Mdm 2 cooperate to inhibit p 53 activity in proliferating and quiescent cells in vivo . ^^^ The Mdm 2 and Mdm 4 oncoproteins are key negative regulators of the p 53 tumor suppressor . ^^^ Here , we combined a p 53 knock in allele , in which p 53 is silenced by a transcriptional stop element flanked by loxP sites , with the mdm 2 and mdm 4 null alleles . ^^^ This approach allows Cre mediated conditional p 53 expression in tissues in vivo and cells in vitro lacking Mdm 2 , Mdm 4 , or both . ^^^ Using this strategy , we show that Mdm 2 and Mdm 4 are essential in a nonredundant manner for preventing p 53 activity in the same cell type , irrespective of the proliferation / differentiation status of the cells . ^^^ |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| NA |
|
| Interacting proteins: O15151 and Q00987 |
Pubmed |
SVM Score :0.0 |
| NA |
|