Pubmed abstracts for Protein-Protein Interaction search result :


Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.52304717
Expression of Bcl XL inhibited the association of Apaf 1 with caspase 9 in mammalian cells . 0.52304717^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.5363661
In the presence of cytochrome c ( Cyt c ) released from mitochondria , Apaf 1 binds to Casp 9 and causes its activation . 0.5363661^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.57440649
Although Bcr Abl prevented interaction of endogenous Apaf 1 with the recombinant prodomain of caspase 9 , it did not affect the association of endogenous caspase 9 with the isolated Apaf 1 caspase recruitment domain ( CARD ) or Apaf 1 lacking WD 40 repeats . 0.57440649^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.70452484
Here we show that physiological levels of nucleotides inhibit the CC initiated apoptosome formation and caspase 9 activation by directly binding to CC on several key lysine residues and thus preventing CC interaction with Apaf 1 . 0.70452484^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Caspase 9 , Bcl XL , and Apaf 1 form a ternary complex . ^^^ An equivalent ternary complex was found to be present in mammalian cells involving Apaf 1 , the mammalian death protease caspase 9 , and Bcl XL , an anti apoptotic member of the Bcl 2 family . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Previous studies have shown that Apaf 1 and caspase 9 in the presence of cytochrome c and dATP can form an initiating complex for an apoptotic protease cascade . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Subsequent modeling of the CARDs of Apaf 1 and caspase 9 , as well as Ced 4 and Ced 3 , showed that the basic / acidic surface polarity is highly conserved , suggesting a general mode for CARD / CARD interaction . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The cytosolic protein APAF 1 , human homolog of C . elegans CED 4 , participates in the CASPASE 9 ( CASP 9 ) dependent activation of CASP 3 in the general apoptotic pathway . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Recent studies have demonstrated that Apaf 1 is the adaptor molecule which in the presence of cytosolic cytochrome c ( cyt c ) and dATP interacts with procaspase 9 , resulting in the sequential cleavage and activity of caspase 9 and caspase 3 , followed by apoptosis . ^^^ Coexpression of the catalytically inactive , dominant negative , mutant caspase 9 , XIAP , or treatment with the caspase inhibitor , zVAD , significantly inhibited the increase in apoptosis of HL 60 / Apaf 1 cells ( P < 0 . 01 ) . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Here , we show that this activation requires a previously identified apoptosis promoting complex consisting of caspase 9 , APAF 1 , and cytochrome c . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Importantly , Diva interacted with Apaf 1 , an adapter molecule that activates caspase 9 , a central death protease of the apoptotic pathway . ^^^ Thus , Diva represents a novel type of proapoptotic Bcl 2 homologue that promotes apoptosis independently of the BH 3 region through direct binding to Apaf 1 , thus preventing Bcl XL from binding to the caspase 9 regulator Apaf 1 . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
A regulator of apoptosis , Apaf 1 , binds to and activates pro casp 9 in the presence of cytochrome c and dATP , a requirement that is bypassed by deletion of the WD 40 repeats located in the C terminal half of Apaf 1 . ^^^ In this report , we used constitutively active Apaf 1 mutant lacking the WD 40 repeat region to study the mechanism and regulation of pro casp 9 activation . ^^^ Mutational analysis revealed that only a small portion of the CED 4 homologous region ( residues 456 559 ) could be deleted without destroying the ability of Apaf 1 ( 1 559 ) to activate pro casp 9 . ^^^ Disruption of Apaf 1 self association by deletion ( Delta 109 559 ) or mutation of the P loop region ( K149R ) abrogated Apaf 1 mediated pro casp 9 activation . ^^^ Forced oligomerization of the caspase recruitment domain of Apaf 1 was sufficient for pro casp 9 activation . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
More importantly , Boo interacts with Apaf 1 and forms a multimeric protein complex with Apaf 1 and caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Moreover , caspase 9S inhibited apoptosis induced by tumor necrosis factor ( TNF ) alpha , TNF factor related apoptosis inducing ligand ( TRAIL ) , Bax , or Fas associated death domain containing protein ( FADD ) as well as the combination of Apaf 1 and caspase 9 . ^^^ In vitro binding assays demonstrated that caspase 9S binds to Apaf 1 and blocks the binding of caspase 9 to Apaf 1 . ^^^ Thus , caspase 9S acts as a dominant negative inhibitor of caspase 9 activation , at least in part , by blocking Apaf 1 caspase 9 interaction . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In the cytosol , cytochrome c binds to the CED 4 homologue , Apaf 1 , thereby triggering Apaf 1 mediated activation of caspase 9 . ^^^ In vitro association assays confirmed that caspase 9 selectively bound to Apaf 1 , whereas caspases 1 , 2 , 3 , 6 , 7 , 8 , and 10 did not . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Caspase 9b can interact with the caspase recruitment domain of Apaf 1 , and like the active site mutant of caspase 9 , it can inhibit multiple forms of apoptosis , including those triggered by oligomerization of death receptors . ^^^ It can also block activation of caspase 9 and 3 by Apaf 1 in an in vitro cytochrome c dependent caspase activation assay . ^^^ These results suggest that caspase 9b functions as an endogenous apoptosis inhibitory molecule by interfering with the formation of a functional Apaf 1 caspase 9 complex . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In the cytosol , cytochrome c combines with APAF 1 in the presence of ATP to activate caspase 9 that , in turn , activates effectors caspases such as caspase 3 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apaf 1 and caspase 9 in p 53 dependent apoptosis and tumor inhibition . ^^^ Caspase 9 and its cofactor Apaf 1 were found to be essential downstream components of p 53 in Myc induced apoptosis . ^^^ Like p 53 null cells , mouse embryo fibroblast cells deficient in Apaf 1 and caspase 9 , and expressing c Myc , were resistant to apoptotic stimuli that mimic conditions in developing tumors . ^^^ Inactivation of Apaf 1 or caspase 9 substituted for p 53 loss in promoting the oncogenic transformation of Myc expressing cells . ^^^ These results imply a role for Apaf 1 and caspase 9 in controlling tumor development . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
CIPER formed homodimers via its CARD and interacted with viral E 10 but not with several apoptosis regulators containing CARDs including ARC , RAIDD , RICK , caspase 2 , caspase 9 , or Apaf 1 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In the early process of apoptosis , cytochrome c , which usually is involved in the respiratory chain , is released from mitochondria into the cytosol , then bind to Apaf 1 , a homologue of CED 4 of nematoda , to process pro caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
These observations also confirm the existence of two pathways for Fas mediated apoptotic signal transduction and suggest that the Apaf 1 ( Ced 4 homologue ) system for caspase 9 activation operates in an ATP dependent manner in vivo . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Nod 1 , an Apaf 1 like activator of caspase 9 and nuclear factor kappaB . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
However , unlike the truncated Apaf 530 complex , the full length Apaf 1 complex can release the mature caspase 9 after processing . ^^^ These observations indicate that cytochrome c and dATP are required for oligomerization of Apaf 1 and suggest that the WD 40 domain plays an important role in oligomerization of full length Apaf 1 and the release of mature caspase 9 from the Apaf 1 oligomeric complex . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Mature caspase 9 is derived from its procaspase precursor as a result of recruitment by the activating factor Apaf 1 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Role of cytochrome c and dATP / ATP hydrolysis in Apaf 1 mediated caspase 9 activation and apoptosis . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apoptotic protease activating factor 1 ( Apaf 1 ) has been identified as a proximal activator of caspase 9 in cell death pathways that trigger mitochondrial damage and cytochrome c release . ^^^ The mechanism of Apaf 1 action is unclear but has been proposed to involve the clustering of caspase 9 molecules , thereby facilitating autoprocessing of adjacent zymogens . ^^^ Here we show that Apaf 1 can dimerize via the CED 4 homologous and linker domains of the molecule providing a means by which Apaf 1 can promote the clustering of caspase 9 and facilitate its activation . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In mammals , apoptotic protease activating factor 1 ( Apaf 1 ) , cytochrome c , and dATP activate caspase 9 , which initiates the postmitochondrial mediated caspase cascade by proteolytic cleavage / activation of effector caspases to form active approximately 60 kDa heterotetramers . ^^^ The larger aposome complex ( M ( r ) = approximately 700 , 000 ) contained Apaf 1 and processed caspase 9 , 3 , and 7 . ^^^ The smaller microaposome complex ( M ( r ) = approximately 200 , 000 300 , 000 ) contained active caspase 3 and 7 but little if any Apaf 1 or active caspase 9 . ^^^ During caspase activation , Apaf 1 , caspase 9 , and the effector caspases redistributed and formed the aposome . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Human platelets contained caspase 9 , caspase 3 , and the caspase activators APAF 1 and cytochrome c as shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
This renders Apaf 1 competent to recruit and activate the cell death initiator caspase , pro caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Solution structure of Apaf 1 CARD and its interaction with caspase 9 CARD : a structural basis for specific adaptor / caspase interaction . ^^^ Direct recruitment and activation of caspase 9 by Apaf 1 through the homophilic CARD / CARD ( Caspase Recruitment Domain ) interaction is critical for the activation of caspases downstream of mitochondrial damage in apoptosis . ^^^ Here we report the solution structure of the Apaf 1 CARD domain and its surface of interaction with caspase 9 CARD . ^^^ On the basis of the identified functional residues of Apaf 1 CARD and the surface charge complementarity , we propose a model of CARD / CARD interaction between Apaf 1 and caspase 9 . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The caspase recruitment domain ( CARD ) of Apaf 1 binds to the CARD of caspase 9 to trigger a proteolytic cascade that leads to apoptotic cell death . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Caspase 9 and APAF 1 form an active holoenzyme . ^^^ Activation of caspase 9 , which mediates oncogene and drug induced apoptosis , requires binding to the protein APAF 1 . ^^^ We found that the proteolytic activity of caspase 9 in a complex with APAF 1 is several orders of magnitude higher than that of the free enzyme . ^^^ Thus , this complex functions as a holoenzyme in which caspase 9 is the catalytic subunit and APAF 1 its allosteric regulator . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apaf 1 , by binding to and activating caspase 9 , plays a critical role in apoptosis . ^^^ Oligomerization of Apaf 1 , in the presence of dATP and cytochrome c , is required for the activation of caspase 9 and produces a caspase activating apoptosome complex . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
P ( GFLG ) DOX effectively killed both types of tumors inducing apoptosis and necrosis through the activation of p 53 , Apaf 1 , caspase 9 , c fos , or c jun pathways , and the downregulation of the bcl 2 gene . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The role of Apaf 1 , caspase 9 , and bid proteins in etoposide or paclitaxel induced mitochondrial events during apoptosis . ^^^ In this report , we demonstrate that in HL 60 / Apaf 1 cells , the activity of caspase 9 and 3 induced by Apaf 1 overexpression was associated with a significant increase ( 5 fold ) in the cytosolic accumulation of cytochrome c ( cyt c ) , loss of mitochondrial membrane potential ( deltapsim ) , and an increase in the reactive oxygen species . ^^^ This conclusion is supported by the observation that in HL 60 / Apaf 1 cells , ectopic expression of dominant negative caspase 9 , its inhibitory short isoform caspase 9b , or XIAP or treatment with the caspase inhibitor zVAD ( 50 microM ) inhibited Apaf 1 induced caspase 8 and Bid cleavage , mitochondrial deltapsim , release of cyt c , and apoptosis . ^^^ These results indicate that Apaf 1 overexpression lowers the apoptotic threshold by activating caspase 9 and caspase 3 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Previous reports have suggested at least two distinct mechanisms : Bcl 2 and Bcl xL may inhibit either the formation of the cytochrome c / Apaf 1 / caspase 9 apoptosome complex ( by preventing cytochrome c release from mitochondria ) or the function of this apoptosome ( through a direct interaction of Bcl 2 or Bcl xL with Apaf 1 ) . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Transduction of Apaf 1 or caspase 9 induces apoptosis in A 172 cells that are resistant to p 53 mediated apoptosis . p 53 replacement gene therapy has been carried out clinically for cancers with p 53 mutations ; however , some cancers are resistant to p 53 gene therapy . ^^^ We transduced A 172 cells and U 251 cells with the Apaf 1 or caspase 9 genes ; both are downstream components of p 53 mediated apoptosis . ^^^ We found that A 172 cells were highly sensitive to Apaf 1 and caspase 9 mediated apoptosis . ^^^ Transduction of Apaf 1 or caspase 9 would override the resistance mechanism of apoptosis in A 172 cells . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Caspase 3 activity was effectively restored by addition of recombinant caspase 9 and APAF 1 proteins , and to a lesser extent by caspase 9 alone , but not by APAF 1 alone . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
An analogous set of core constituents exists in mammalian cells and includes caspase 9 , Apaf 1 , and bcl 2 / xL , respectively . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Cytochrome c promotes caspase 9 activation by inducing nucleotide binding to Apaf 1 . ^^^ These data indicate that the key event in Apaf 1 mediated caspase 9 activation is cytochrome c induced dATP binding to Apaf 1 . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The release of cytochrome c from mitochondria results in the formation of an Apaf 1 caspase 9 apoptosome and induces the apoptotic protease cascade by activation of procaspase 3 . ^^^ Immunodepletion of Hsp 90 depletes Apaf 1 and thereby inhibits cytochrome c mediated activation of caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Consistent with this idea , Aven inhibited the proteolytic activation of caspases in a cell free extract and suppressed apoptosis induced by Apaf 1 plus caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In the apoptosis pathway in mammals , cytochrome c and dATP are critical cofactors in the activation of caspase 9 by Apaf 1 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Once released into the cytosol , cytochrome c binds to its adaptor molecule , Apaf 1 , which oligomerizes and then activates pro caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
To explain why deoxyadenosine and its analogs are toxic to a cell that is not undergoing replicative DNA synthesis , several mechanisms have been proposed , including the direct binding of dATP to the pro apoptotic factor Apaf 1 and the activation of the caspase 9 and 3 pathways . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
However , both Apaf 1 and Apaf 1L elicit cell death when cotransfected with caspase 9 into 293 EBNA cells . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Moreover , immunoblots revealed a strongly reduced expression of the adaptor molecule APAF 1 , which is required for cytochrome c dependent activation of caspase 9 and subsequently caspase 3 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
After 6 days of 9CRA treatment , RARbeta transfectants overexpressed Waf 1 / Cip 1 / Sdi 1 / p 21 , Kip 1 / p 27 , chk 1 , p 300 / CBP , BAX , Bak , Apaf 1 , caspase 3 and caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Activated caspase 8 is known to propagate the apoptotic signal either by directly cleaving and activating downstream caspases or by cleaving the BH 3 Bcl2 interacting protein , which leads to the release of cytochrome c from mitochondria , triggering activation of caspase 9 in a complex with dATP and Apaf 1 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Here we show that metastatic melanomas often lose Apaf 1 , a cell death effector that acts with cytochrome c and caspase 9 to mediate p 53 dependent apoptosis . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The resistant cell lines expressed APAF 1 and caspase 9 , 3 , and 7 ; however , each demonstrated diminished APAF 1 activity relative to the normal ovarian epithelium cell lines . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apoptotic protease activating factor 1 ( Apaf 1 ) is an adaptor molecule essential for caspase 9 activation . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
We have reconstituted the Apaf 1 activated apoptosis mechanism in Sacchromyces cerevisiae such that the presence of a constitutively active form of Apaf 1 together with both Caspase 9 and Caspase 3 results in yeast death . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Subsequently others have also shown that caspase 8 is silenced by methylation in neuroblastoma and peripheral neural ectodermal tumors , and that the caspase 9 regulator Apaf 1 is silenced by methylation in melanoma cell lines and patient samples . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
This result is consistent with observations that gene knockouts of caspase 9 and its activator , Apaf 1 , result in developmental defects in these tissues . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
An homology model of the PYRIN domain of CARD7 / DEFCAP / NAC / NALP1 , a member of the Apaf 1 / Ced 4 family of proteins , was constructed using the three dimensional structures of the FADD and p 75 neurotrophin receptor DDs , and of the Apaf 1 and caspase 9 CARDs , as templates . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Cytochrome c and dATP / ATP induce oligomerization of Apaf 1 into two distinct apoptosome complexes : an approximately 700 kDa complex , which recruits and activates caspases 9 , 3 and 7 , and an approximately 1 . 4 MDa complex , which recruits and processes caspase 9 , but does not efficiently activate effector caspases . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Investigations of apoptosis revealed that cytosolic cytochrome c is associated with a complex of apoptotic protease activating factor 1 ( Apaf 1 ) , an adapter molecule , and caspase 9 to activate caspase 3 . ^^^ Increasing the cellular concentration of Apaf 1 through the transient expression of the gene increased the induction of apoptosis in resistant cells , associated with enhanced activation of caspase 9 , caspase 3 and DNA fragmentation factor . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Specifically , the number of neuronal progenitor cells is abnormally increased in Apaf 1 , caspase 9 , caspase 3 deficient mice . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Injury induced cytochrome c specific cleavage of caspase 9 followed by activation of caspase 3 in mature brain correlated with marked increases in Apaf 1 and caspase 3 mRNA and protein expression . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Here , we show cells deficient for the downstream effectors Apaf 1 , Caspase 9 , or Caspase 3 display only transient protection from `` BH 3 domain only ' ' molecules and die a caspase independent death by mitochondrial dysfunction . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Death receptors , eg , CD 95 ( APO 1 / Fas ) , trigger caspase 8 , and mitochondria release apoptogenic factors ( cytochrome c , Apaf 1 , AIF ) , leading to the activation of caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Released cytochrome c allows the formation of a high molecular weight complex , the apoptosome , which consists of the adapter protein Apaf 1 and caspase 9 , which is activated following recruitment into the apoptosome . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
These observations support a model in which recruitment by Apaf 1 creates high local concentrations of caspase 9 to provide a pathway for dimer induced activation . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The protein levels of pro caspase 8 and pro caspase 3 were not affected by ADR , whereas pro caspase 9 and Apaf 1 were up regulated . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In the present study , we found that mature erythrocytes contain considerable amounts of caspase 3 and 8 , whereas essential components of the mitochondrial apoptotic cascade such as caspase 9 , Apaf 1 and cytochrome c were missing . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Formation of the Apaf 1 / cytochrome c complex precedes activation of caspase 9 during seizure induced neuronal death . ^^^ In this study we examine the in vivo formation of the Apaf 1 / cytochrome c complex and activation of caspase 9 following limbic seizures in the rat . ^^^ These data suggest seizures induce formation of the Apaf 1 / cytochrome c complex prior to caspase 9 activation and caspase 9 may be a potential therapeutic target in the treatment of brain injury associated with seizures . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In mammalian cells , nonreceptor mediated apoptosis occurs predominantly via assembly of a cytochrome c dependent apoptosome complex containing caspase 9 and apoptotic protease activating factor 1 ( Apaf 1 ) . ^^^ This dysfunctional apoptosome activity was not explained by reduced expression levels of caspase 9 or Apaf 1 . ^^^ SKOV 3 , an ovarian cancer cell line with dysfunctional apoptosome activity , retains the ability to form the Apaf 1 oligomer ; however , there is a diminished amount of caspase 9 in the apoptosome . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Co transduction of Apaf 1 and caspase 9 highly enhances p 53 mediated apoptosis in gliomas . ^^^ In this study , we transduced the wild type p 53 gene along with the Apaf 1 and caspase 9 genes via adenovirus vectors into U 251 and U 373MG glioma cells harbouring a mutated p 53 , and evaluated the degree of apoptosis . ^^^ Co induction of Apaf 1 and caspase 9 genes highly enhanced p 53 mediated apoptosis in glioma cells . ^^^ To determine which gene is activated by wild type p 53 induction and , in turn , activates Apaf 1 and caspase 9 , we transduced the Bax , p21 / WAF1 or Fas gene via adenovirus vector to U 251 cells to achieve a similar expression level as that induced by the Adv for p 53 in U 251 cells . ^^^ U 251 cells transduced with Fas concomitant with the Apaf 1 and caspase 9 genes underwent drastic apoptosis . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In the apoptosome , cytochrome c and Apaf 1 activate caspase 9 which subsequently leads to the activation of caspase 3 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
However , other proteins analyzed [ namely , Apaf 1 , Bax , Bid , caspase 3 , caspase 8 , caspase 9 , 10 linked inhibitor of apoptosis protein ( XIAP ) , cellular inhibitor of apoptosis protein ( cIAP ) 1 , cIAP 2 , cytochrome c , Fas , Fas ligand , FLIP , p 53 , and poly ( ADP ribose ) polymerase ] were not affected by either rituximab or cisplatin . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Cytochrome c associates with Apaf 1 and caspase 9 to form the apoptosome . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Methylation and deletion of Apaf 1 and CASP 8 results in the loss of their expression in melanoma and neuroblastoma , respectively , while CASP 9 localization to 1p36 . 1 suggests it is a good candidate tumor suppressor . ^^^ The status of CASP 9 and Apaf 1 expression in numerous neuroblastoma cell lines with / without amplified MYCN and chromosome 1p36 loss of heterozygosity ( LOH ) was therefore examined to test the hypothesis that one or both of these genes are tumor suppressors in neuroblastoma . ^^^ Thus , the CASP 9 or Apaf 1 genes do not appear to function as tumor suppressors in MYCN amplified neuroblastomas . ^^^ Caspase 9 and Apaf 1 are expressed and functionally active in human neuroblastoma tumor cell lines with 1p36 LOH and amplified MYCN . ^^^ Important roles have been suggested for caspase 8 , caspase 9 and Apaf 1 in controlling tumor development and their sensitivity to chemotherapeutic agents . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The release of cytochrome c from mitochondria is necessary for the formation of the Apaf 1 apoptosome and subsequent activation of caspase 9 in mammalian cells . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Oligomerization and activation of caspase 9 , induced by Apaf 1 CARD . ^^^ Apaf 1 facilitates the proteolytic activation of procaspase 9 and maintains the hyperactive state of the processed caspase 9 . ^^^ Here we report that the isolated Apaf 1 caspase recruitment domain ( CARD ) forms a large hetero oligomer with the active caspase 9 . ^^^ The catalytic activity of caspase 9 is significantly enhanced in this complex , demonstrating that Apaf 1 CARD allosterically up regulates caspase 9 activity . ^^^ Point mutations that inactivate the interactions between Apaf 1 CARD and the prodomain of caspase 9 also abolished the formation of this complex . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Furthermore , these results indicate that release of mitochondrial cytochrome c into the cytoplasm within 2 3 h post PDT is a secondary event following the activation of initiator caspase 8 preceding Apaf 1 , caspase 9 and caspase 3 activation , cleavage of PARP and DNA fragmentation . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Caspase 8 and Apaf 1 independent caspase 9 activation in Sendai virus infected cells . ^^^ Caspase 9 activation occurred without the release of cytochrome c from mitochondria and was not dependent on the presence of Apaf 1 or reactive oxygen intermediates . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apoptotic protease activating factor 1 ( Apaf 1 ) and cytochrome c are cofactors critical for inducing caspase 9 activation following stress induced apoptosis . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In contrast , p 75 mediated neuronal death was associated with mitochondrial loss of cytochrome c and required Apaf 1 and caspase 9 , 6 , and 3 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In mitochondrion dependent apoptosis , release of cytochrome C into the cytosol results in the formation of apoptosome containing cytochrome C , Apaf 1 and caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Caspase 2 is not required for thymocyte or neuronal apoptosis even though cleavage of caspase 2 is dependent on both Apaf 1 and caspase 9 . ^^^ Caspase 2 processing does not occur in thymocytes lacking Apaf 1 or caspase 9 , suggesting that in this cell type , activation of caspase 2 occurs downstream of apoptosome formation . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Mouse mutants that have helped to define the mammalian apoptosis execution machinery , including animals lacking Apaf 1 , caspase 3 and caspase 9 , are also described . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
These data demonstrate a novel mechanism of apoptosis in which an increase in Apaf 1 levels results in direct activation of caspase 9 without mitochondrial damage , leading to the initiation of a caspase cascade . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Eiger induced cell death requires the caspase 9 homolog DRONC and the Apaf 1 homolog DARK . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Thus , XIAP ' s capacity to maintain inhibition of caspase 9 within the Apaf 1 apoptosome is influenced by its ability to simultaneously inhibit active caspase 3 , and depending upon the apoptotic stimulus , inhibition of caspase 9 or 3 is essential for XIAP ' s anti apoptotic activity . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apaf 1 , another cytosolic protein of the apoptotic cascade , also migrates to the permeabilized mitochondria and also co localizes with caspase 9 and cytochrome c in the cytosol or mitochondria of denucleating cells , thus providing evidence for the formation of an ' apoptosome ' in these cells , as in apoptotic cells . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apoptotic signaling during oxygen deprivation occurs through the release of cytochrome c and apaf 1 mediated caspase 9 activation . ^^^ Pro apoptotic Bcl 2 family members such as bax or bak are clearly required to initiate cytochrome c / apaf 1 / caspase 9 mediated cell death during oxygen deprivation . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apoptosis initiated by Bcl 2 regulated caspase activation independently of the cytochrome c / Apaf 1 / caspase 9 apoptosome . ^^^ Mammalian caspase 9 and its activator Apaf 1 were thought to be essential , because mice lacking either of them display neuronal hyperplasia and their lymphocytes and fibroblasts seem resistant to certain apoptotic stimuli . ^^^ Because Apaf 1 requires cytochrome c to activate caspase 9 , and Bcl 2 prevents mitochondrial cytochrome c release , Bcl 2 is widely believed to inhibit apoptosis by safeguarding mitochondrial membrane integrity . ^^^ Our results suggest a different , broader role , because Bcl 2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli , but the absence of Apaf 1 or caspase 9 did not . ^^^ Caspase activity was still discernible in cells lacking Apaf 1 or caspase 9 , and a potent caspase antagonist both inhibited apoptosis and retarded cytochrome c release . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Diverse apoptotic stimuli release holocytochrome c from mitochondria , allowing holocytochrome c to bind apoptotic protease activating factor 1 ( Apaf 1 ) , which in turn binds caspase 9 both activating this caspase and forming an Apaf 1 / caspase 9 holoenzyme . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The knock out of essential caspase activators ( Apaf 1 or caspase 9 ) or the knock out of a mitochondrial caspase independent death effector ( AIF ) does not abolish Vpr mediated killing . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The caspase cascade is activated by the release of cytochrome c , which is initiated by the formation of apoptosomes consisting of procaspase 9 , Apaf 1 and cytochrome c in the presence of dATP , and results in the activation of caspase 9 and caspase 3 , thereby leading to apoptosis . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
In this pathway , cytochrome c released from mitochondria facilitates the formation of an Apaf 1 apoptosome that recruits and activates caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Regulation of the Apaf 1 / caspase 9 apoptosome by caspase 3 and XIAP . ^^^ The apoptosome is a multiprotein complex comprising Apaf 1 , cytochrome c , and caspase 9 that functions to activate caspase 3 downstream of mitochondria in response to apoptotic signals . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Instead , we observed that caspase 9 , Apaf 1 and caspase 3 were all partially truncated by calpain under these conditions . ^^^
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Like the structurally related apoptotic protease activating factor 1 ( APAF 1 ) , which is responsible for the activation of caspase 9 , the NALP 1 protein forms a large , signal induced multiprotein complex , the inflammasome , resulting in the activation of pro inflammatory caspases . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Recent studies implicate that TBT induces apoptosis via the mitochondrial signaling pathway that is characterized by the formation of a high molecular weight complex ( apoptosome ) containing the adapter protein Apaf 1 and active caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Theoretically , procaspase 9 might be activated in the mitochondria in a cytochrome c / Apaf 1 dependent manner , or activated caspase 9 and 3 may translocate to the mitochondria , or the mitochondrially localized procaspases may be activated by the translocated active caspases . ^^^ Here we present evidence that the mitochondrially localized active caspase 9 and 3 result mostly from translocation from the cytosol ( into the intermembrane space ) and partly from caspase mediated activation in the organelle rather than from the Apaf 1 mediated activation . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apaf 1 , Bcl xL , cytochrome c , and caspase 9 form the critical elements for cerebral vascular protection by erythropoietin . ^^^ Consistent with the modulation of Apaf 1 and the release of cytochrome c , EPO also inhibits the activation of caspase 9 and caspase 3 like activities . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Studies on apoptosis , the well characterized form of programmed cell death led to the identification of a central tripartite death switch i . e . apoptosome consisting of Apaf 1 , Apaf 2 and Apaf 3 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Oligomerization induced procaspase 9 activation , both within the apoptosome and in artificial systems , requires stable homophilic association of the protease domains , raising the possibility that the function of Apaf 1 is not only to oligomerize procaspase 9 but also to maintain the interaction of the caspase 9 protease domain after processing . ^^^
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This review focuses on novel strategies to induce apoptosis in glioma cells by transduction with adenoviral vectors carrying a variety of apoptosis related genes , including Fas ligand , Fas , FADD , caspase 8 , p 53 , p33ING1 , p73alpha , Bax , Apaf 1 , caspase 9 , IkappaBdN , caspase 3 , Bcl 2 , and Bcl 10 ( L ) . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apaf 1 , which executes programmed cell death in the caspase 9 related pathway , was detected in the cells exhibiting caspase 9 activity , and our results suggest that Apaaf 1 / caspase 9 activates caspase 3 in kidney organogenesis . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Cytochrome c binds to Apaf 1 and dATP and recruits and cleaves pro caspase 9 in the apoptosome . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Expression and activity of Apaf 1 and caspase 9 in granulosa cells during follicular atresia in pig ovaries . ^^^ Both mRNAs of caspase 9 and apoptotic protease activating factor 1 ( Apaf 1 ) , which are major signal transducing components in the mitochondrial pathway , were detected in granulosa cells in healthy , early atretic and progressed atretic follicles by RT PCR . ^^^ No changes in the expression of Apaf 1 mRNA were seen during follicular atresia , but the expression of caspase 9 mRNA increased during atresia . ^^^ Apaf 1 protein was steadily detected in granulosa cells prepared from healthy , early atretic and progressed atretic follicles by western blot analysis , but high expression of the precursor of caspase 9 ( procaspase 9 ) was detected only in granulosa cells of healthy follicles . ^^^ These results indicate that the mitochondrial signalling pathway , which is mediated by Apaf 1 and caspase 9 , plays a crucial role in determining the fate of granulosa cells during atresia in pig ovaries . . ^^^
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However , we found that cytochrome c dependent proteolysis and activation of caspase 9 could not be restored in an adult cell free system because of an age related decrease in the expression of Apaf 1 in the normal developing mouse retina . ^^^
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The cell death pathway initiated by survivin targeting was mapped with respect to cytochrome c release , changes in mitochondrial transmembrane potential , and apoptosome requirements using mouse embryonic fibroblasts deficient in Apaf 1 or caspase 9 . ^^^ Cell death induced by survivin targeting exhibited the hallmarks of mitochondrial dependent apoptosis with release of cytochrome c and loss of mitochondrial transmembrane potential and was suppressed in Apaf 1 or caspase 9 knockout mouse embryonic fibroblasts . ^^^
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Myocardial cells did not express apoptotic protease activating factor 1 ( Apaf 1 ) , the allosteric activator of caspase 9 acting downstream of cytochrome c release . ^^^
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Early processing of caspase 9 also occurred in Apaf 1 knockout murine fibroblasts in response to TNF receptor occupation . ^^^
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In particular , CD26 / DPPIV presence is associated with increased susceptibility to the mitochondrial pathway of apoptosis , documented by enhanced cleavage of poly ( ADP ribose ) polymerase ( PARP ) , caspase 3 and caspase 9 , Bcl xl , and Apaf 1 , as well as increased expression of death receptor 5 ( DR 5 ) . ^^^
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The release of mitochondrial apoptogenic proteins , such as cytochrome c , into the cytoplasm leading to Apaf 1 dependent activation of caspase 9 is a key event in this pathway . ^^^
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Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf 1 and Caspase 9 apoptosome expression . ^^^ These cells did not express the apoptotic protease activating factor 1 ( Apaf 1 ) and Caspase 9 genes that encode for the proteins that form the `` apoptosome ' ' complex . ^^^ The disappearance of the Apaf 1 and Caspase 9 gene was recovered by a cellular signaling inhibitor of protein kinase C , phosphatidylinositol 3 phosphate kinase and mitogen activated protein kinase of the in vitro cultured human fibrosarcoma HT 1080 line . ^^^ The results might indicate a novel route by which tumor cells protect themselves with products , such as AMF , and proliferate despite various stresses and chemical insults ; AMF regulates expression of Apaf 1 and caspase 9 genes via a complex signaling pathway and indirectly regulates formation of the apoptosome . . ^^^
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Conversely , DNA damage induced reactive oxygen species generation was inhibited significantly by gene disruption of p 53 , Apaf 1 , or caspase 9 , and combined deficiency of Bax and Bak , but not by caspase 3 or caspase 6 deficiency . ^^^
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When the extract was activated by cytochrome c , caspase 3 recruitment to the apoptosome was not observed , although apoptotic protease activating factor 1 ( Apaf 1 ) , caspase 9 , and 10 linked inhibitor of apoptosis protein ( XIAP ) existed in the apoptosome . ^^^
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A fraction of PSR knockout mice manifested a hyperplasic brain phenotype resembling that of mice deficient in the cell death associated genes encoding Apaf 1 , caspase 3 , and caspase 9 , which suggests that phagocytes may also be involved in promoting apoptosis . ^^^
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Of the four nonclear cell RCC that could be included , both oncocytomas gave no response to cytochrome c ( in one case , no Apaf 1 was detected ) , one chromophobe RCC lacked caspase 9 and failed to activate caspase 3 in response to cytochrome c , and one papillary RCC showed good caspase activation despite the lack of caspase 7 . ^^^
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Evidence supporting the involvement of K+ efflux , the apoptosome ( caspase 9 , apoptosis activating factor 1 , APAF 1 , and Bcl xL ) , caspase 3 , c jun kinase , and p 53 in the p75NTR cell death pathway is discussed and regulatory roles for the p75NTR ectodomain and death domain are proposed . ^^^
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Caspase 9 , an initiator caspase , is then recruited to the complex by binding to Apaf 1 through CARD CARD ( caspase recruitment domain ) interactions to form a holoenzyme complex . ^^^ Subsequently , the Apaf 1 / caspase 9 holoenzyme complex recruits the effector caspase 3 via an interaction between the active site cysteine in caspase 9 and the critical aspartate , which is the cleavage site for generating the large and small subunits of caspase 3 that constitute the activated form of caspase 3 . ^^^
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Apaf 1 and caspase 9 do not act as tumor suppressors in myc induced lymphomagenesis or mouse embryo fibroblast transformation . ^^^ Based on experiments with cultured fibroblasts , the apoptosis regulators caspase 9 and Apaf 1 are hypothesized to function as tumor suppressors . ^^^ To investigate their in vivo role in lymphomagenesis , an IgH enhancer driven c myc transgene was crossed onto Apaf 1 ( / ) and caspase 9 ( / ) mice . ^^^ Due to perinatal lethality , Emu myc transgenic Apaf 1 ( / ) or caspase 9 ( / ) fetal liver cells were used to reconstitute lethally irradiated recipient mice . ^^^ Surprisingly , no differences were seen in rate , incidence , or severity of lymphoma with loss of Apaf 1 or caspase 9 , and Apaf 1 was not a critical determinant of anticancer drug sensitivity of c myc induced lymphomas . ^^^
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Processing of procaspase 9 occurred in Apaf 1 ( / ) myoblasts but not fibroblasts , and ablation of Casp 9 prevented drug induced apoptosis in both cell types . ^^^ Coupling of caspase 9 to Apaf 1 in response to loss of pRb or cytotoxic drugs is cell type specific . ^^^ Deregulation of the Rb pathway by overexpression of E2F1 also induced caspase 9 dependent , Apaf 1 independent apoptosis in myoblasts . ^^^ Therefore , loss of pRb elicits apoptosome dependent and apoptosome independent cell death , and the requirement and coupling of caspase 9 to Apaf 1 are both context dependent . . ^^^
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In spite of the remarkable decrease of Apaf 1 in apoptotic cells , caspase 9 was found to be processed and enzymatically active . ^^^ Unexpectedly , the inhibition afforded by ac DEVD CHO on several components , that is , caspase 3 / 7 and caspase 9 activities , and Apaf 1 proteolytic degradation , did not abrogate the apoptotic morphology and cell detachment , nor the proteolytic degradation of crucial targets , such as poly ( ADP ribose ) polymerase ( PARP ) and lamin B . ^^^
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Recent studies indicate that the apoptosome is a wheel like structure consisting of seven molecules of Apaf 1 and a similar number of caspase 9 dimers . ^^^
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Assembly of the apoptosome in response to mitochondrial permeabilization , the hallmark of the intrinsic apoptotic pathway , involves binding of cytochrome c to Apaf 1 , recruitment and auto processing of the apical / signaling pro caspase 9 , and coupled activation of downstream / executioner caspases like caspase 3 . ^^^ Recently , we have demonstrated that caspase 9 can be activated in Apaf 1 mutant primary myoblasts , but not fibroblasts , in response to stimuli that are known to act via the mitochondria . ^^^ Thus , apoptosomal activation of caspase 9 seems to represent only one of the routes for its activation ; other pathways , some of which are yet to be discovered , can bypass the requirement for Apaf 1 and activate caspase 9 in a tissue and context specific manner . . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Apoptosis protease activating factor 1 ( Apaf 1 ) , which plays a central role in the formation of the apoptosome , is absent or poorly expressed ( because of a transcriptional silencing by methylation ) in a substantial percentage of metastatic melanomas and melanoma cell lines , which are unable to activate caspase 9 and execute the mitochondrial pathway of apoptosis . ^^^ Our data also indicate that the inhibition afforded by ac DEVD CHO on several components ( i . e . , caspase 3 / 7 and caspase 9 activities ) , and Apaf 1 proteolytic degradation , does not significantly abrogate either the apoptotic morphology or the cleavage of canonical targets , such as poly ( ADP ribose ) polymerase ( PARP ) and lamin B . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Cytochrome c and dATP dependent formation of Apaf 1 / caspase 9 complex initiates an apoptotic protease cascade . ^^^ Caspase 9 and Apaf 1 bind to each other via their respective NH 2 terminal CED 3 homologous domains in the presence of cytochrome c and dATP , an event that leads to caspase 9 activation . ^^^
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Taurine inhibits apoptosis by preventing formation of the Apaf 1 / caspase 9 apoptosome . ^^^ Taurine loading also suppressed the formation of the Apaf 1 / caspase 9 apoptosome and the interaction of caspase 9 with Apaf 1 . ^^^ These findings demonstrate that taurine effectively prevents myocardial ischemia induced apoptosis by inhibiting the assembly of the Apaf 1 / caspase 9 apoptosome . . ^^^
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APIP is highly expressed in skeletal muscle and heart and binds to the CARD of Apaf 1 in competition with caspase 9 . ^^^ Taken together , these results suggest that APIP functions to inhibit muscle ischemic damage by binding to Apaf 1 in the Apaf 1 / caspase 9 apoptosis pathway . . ^^^
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Among the molecules that we discuss are elements of the extrinsic death pathway like CD 95 ( APO 1 / Fas ) , FADD , FLIPs , FLICE , other apical caspases , components of the intrinsic apoptotic pathway like Apaf 1 , caspase 9 , and modulators of apoptotic pathways like IAPs , Smac / DIABLO , OMI / HtrA2 , and other apoptosis regulating proteins . ^^^
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While this activation of caspase 3 was paralleled by an elevated caspase 9 expression at 9 h post irradiation , there was no major induction in Apaf 1 or cytochrome c release . ^^^
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Loss of expression of the apoptosis protease activator protein 1 ( APAF 1 ) in human melanoma is thought to promote resistance to programmed cell death by preventing caspase 9 activation . ^^^ Treatment with cisplatin , camptothecin , etoposide , betulinic acid , celecoxib , 1400W , and staurosporine promoted enzymatic activity not only of caspases 2 , 8 , and 3 but also of caspase 9 in both APAF 1 ( + ) and APAF 1 ( ) tumor cells . ^^^ Moreover , drug induced caspase 9 enzymatic activity could be not only partially but significantly reduced by caspase 2 , 3 , and 8 specific inhibitors in both APAF 1 ( + ) and APAF 1 ( ) tumor cells . ^^^
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In the latter , mitochondrial damage results in cytochrome c release and formation of the apoptosome , a multimeric protein complex containing Apaf 1 , cytochrome c , and caspase 9 . ^^^
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Thus , we conclude that apoptosis induced by nucleoside analogues is independent from death receptor signaling as well as from a proposed direct effect on APAF 1 , but rather follows the mitochondrial signaling pathway of cytochrome c release and subsequent processing of caspase 9 and 3 . . ^^^
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Caspase 9 and Apaf 1 were expressed and cytochrome c released from mitochondria upon serum withdrawal . ^^^
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This dreadful role is realized through the relocalization of mitochondrial cyt c to the cytoplasm where it interacts with Apaf 1 in forming apoptosomes and mediating caspase 9 activation . ^^^
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In the third trimester of gestation , there is an increased expression of mitochondrial pathway proteins , viz . , Apaf 1 and caspase 9 . ^^^ In particular , Apaf 1 and caspase 9 are distributed near to the nuclear envelope suggesting an important role for these two proteins in disrupting the nuclear cytoplasmic barrier . . ^^^
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The anti apoptotic effect of AMF has been described by other authors who have shown that the AMF over expressing cells were resistant to mitomycin C induced apoptosis showing regression of Apaf 1 and caspase 9 dependent on PI3K and MAP kinase . ^^^
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In 17 patients with neurogenic muscular atrophy , we studied the expression of the apoptosis mediators APAF 1 / caspase 9 and degrading caspases 2 , 3 , and 7 by immunohistochemical and western blot analyses . ^^^ Muscle with neurogenic atrophy showed distinct upregulation of caspase 9 and 7 and no expression for APAF 1 ( apoptosis protease activating factor 1 ) and caspase 2 and 3 . ^^^
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Induction of the intrinsic pathway has been studied extensively and involves release of free E2F and direct transcriptional activation of E2F responsive apoptotic genes such as ARF , APAF 1 , and CASP 9 . ^^^
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Apoptotic protease activating factor 1 ( Apaf 1 ) is a cell death effector that acts with cytochrome c and caspase 9 to mediate apoptosis . ^^^
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Protein kinase A regulates caspase 9 activation by Apaf 1 downstream of cytochrome c . ^^^ A critical component of the intrinsic apoptotic pathway is caspase 9 , which is activated by Apaf 1 in the apoptosome , a large complex assembled in response to release of cytochrome c from mitochondria . ^^^ Importantly , protein kinase A inhibits cytochrome c dependent recruitment of procaspase 9 to Apaf 1 but not activation of caspase 9 by a constitutively activated form of Apaf 1 . ^^^
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The antiapoptotic proteins , Bcl 2 and Bcl xl , were downregulated by GSP , whereas the expression of the pro apoptotic protein , Bax , and the levels of cytochrome c release , Apaf 1 , caspase 9 , and cleaved caspase 3 ( p 19 and p 17 ) were markedly increased in JB 6 C141 cells . ^^^
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In addition , BID , BCL 2 , APAF 1 , CASP 2 , CASP 3 and CASP 9 were found to be preferentially expressed in tumours with favourable biology , whereas CDKN1A ( p 21 ) , IL2RA , and MCL 1 , were found to be preferentially expressed in NB tumours with unfavourable biology . ^^^
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Nevertheless , acidic pH did not prevent the recruitment and association of caspase 9 by Apaf 1 , as shown by coimmunoprecipitation . ^^^
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ATP or dATP is a required activator of Apaf 1 for formation of the Apoptosome and thereby activation of caspase 9 ( Csp 9 ) [ Zou , H . , Henzel , W . ^^^
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During apoptosis , Apaf 1 binds to cytochrome c and in the presence of ATP / dATP forms an apoptosome , leading to the recruitment and activation of the initiator caspase , caspase 9 ( ref . 2 ) . ^^^
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Here we used embryonic fibroblasts derived from mice deficient in the multidomain proapoptotic members of the Bcl 2 family ( Bax and Bak ) and the apoptotic components of the apoptosome ( Apaf 1 and caspase 9 ) to unravel the cascade of events by which Bcl 10 ( S ) promotes apoptosis . ^^^
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Altering cellular GSH with ethacrynic acid or N acetylcysteine , respectively , exacerbated or protected against dPC 12 apoptosis . dPC 12 apoptosis was mediated by caspase 9 and 3 activation and apoptosis protease activator protein 1 ( Apaf 1 ) expression . ^^^
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Inhibition of hepatitis C virus core protein expression in immortalized human hepatocytes induces cytochrome c independent increase in Apaf 1 and caspase 9 activation for cell death . ^^^ Apaf 1 is frequently deregulated under various pathologic conditions , and examination of AS Core expressing apoptotic cells indicated a significant increase in the level of Apaf 1 , which coincided with caspase 9 activation . ^^^ Knockdown of Apaf 1 or the transcriptional regulatory proteins , E2F1 or p 53 , by small interfering RNA ( siRNA ) duplexes inhibited the activation of caspase 9 and enhanced cell viability in AS Core expressing cells . ^^^
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In parallel experiments , the expression of genes related to apoptosis , BCL 2 , BCLXL , BAX , P 53 , APAF 1 , Caspase 3 , and Caspase 9 , was determined by RT PCR . ^^^
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However , the catalytic activity of the dimeric caspase 9 is only a small fraction of that for the Apaf 1 activated caspase 9 . ^^^ Furthermore , in contrast to the WT caspase 9 , the activity of the dimeric caspase 9 can no longer be significantly enhanced in an Apaf 1 dependent manner . ^^^ These findings suggest that dimerization of caspase 9 may be qualitatively different from its activation by Apaf 1 , and in conjunction with other evidence , posit an induced conformation model for the activation of initiator caspases . . ^^^
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Examined apoptosis related genes included tumor suppressor genes p 53 , p 53 ; mouse double minute 2 , MDM 2 ; cyclin dependent kinase inhibitor p 21 ( WAF 1 ) , p 21 ( waf ) ; Bcl 2 associated protein 10 , BAX ; apoptotic protease activating factor 1 , Apaf 1 ; Caspase 9 and serine / threonine protein kinase , PKB . ^^^
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Cyt c then initiates the formation of the apoptosome , comprising Apaf 1 ( apoptotic protease activating factor 1 ) , caspase 9 and other cofactors . ^^^
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These responses were associated with prominent changes in expression of several proteins that regulate apoptosis ( Bcl 2 , Bax , Apaf 1 , Caspase 9 cleavage , PARP cleavage ) and cellular growth , differentiation and stress response ( p 53 , Hsp 27 , NF kappaB ) . ^^^
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We further demonstrate that Cdk 5 can be activated in the absence of p 53 , Apaf 1 , caspase 9 , and 3 during cell death , indicating that its activation relates more to cell death than to a specific pathway of apoptosis . . ^^^
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RESULTS : Reverse transcription PCR revealed the detection of apoptosis related m RNAs as follows ( group A compared to group B ) : Apaf 1 0 % / 0 % ; Bcl 2 0 % / 35 % ; Bim 0 % / 9 % ; Bag 1 0 % / 9 % ; p 53 0 % / 4 % ; casp 3 11 % / 52 % ; casp 5 59 % / 48 % ; casp 8 44 % / 22 % ; casp 9 4 % / 9 % ; Bax 81 % / 52 % ; Bad 96 % / 56 % , and c myc 89 % / 96 % . ^^^
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APAF 1 couples cytochrome c release from the mitochondria to caspase 9 activation and has been considered a central adaptor in the intrinsic pathway of programmed cell death . ^^^
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METHODS : Tissue specimens of 12 tooth germs , 41 benign ameloblastomas , and five malignant ameloblastomas were examined by reverse transcriptase polymerase chain reaction ( RT PCR ) and immunohistochemistry to determine the expression of cytochrome c , apoptotic protease activating factor 1 ( APAF 1 ) , caspase 9 , and apoptosis inducing factor ( AIF ) . ^^^ RESULTS : The mRNA expression of APAF 1 , caspase 9 , and AIF was detected in all samples of normal and neoplastic odontogenic tissues . ^^^ Immunohistochemical reactivity for cytochrome c , APAF 1 , caspase 9 , and AIF was detected in both normal and neoplastic odontogenic tissues . ^^^ Expression of cytochrome c and AIF was evident in odontogenic epithelial cells neighboring the basement membrane , and APAF 1 and caspase 9 were detected in most odontogenic epithelial cells . ^^^ CONCLUSION : Expression of cytochrome c , APAF 1 , caspase 9 , and AIF in tooth germs and ameloblastomas suggests that the mitochondria mediated apoptotic pathway has a role in apoptotic cell death of normal and neoplastic odontogenic epithelium . ^^^
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Specifically , overexpression of CRABP 2 , in the absence of RA , up regulated the expression of Apaf 1 and triggered caspase 7 and caspase 9 cleavage . ^^^
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In addition , the degree of colocalization between Apaf 1 and fluorescently labeled caspase 9 significantly increased during the same period . ^^^
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The molecular phenotypes of Apaf 1 variants were determined by in vitro reconstruction of the apoptosome complex in which Apaf 1 activates caspase 9 and thus initiates a cascade of proteolytic events leading to apoptotic destruction of the cell . ^^^
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Activation of the route from cell surface requires the cellular components that include membrane receptors , adaptor proteins such as TRADD and FADD , and caspase 8 , while activation of the other from mitochondria requires Apaf 1 , caspase 9 , and cytosolic cytochrome c . ^^^
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Caspase 9 is a critical component of the mitochondrial or intrinsic apoptotic pathway and is activated by Apaf 1 following release of cytochrome c from mitochondria in response to a variety of stimuli . ^^^
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Apaf 1 and caspase 9 are required for cytokine withdrawal induced apoptosis of mast cells but dispensable for their functional and clonogenic death . ^^^ We previously showed that lymphocyte apoptosis can proceed via a Bcl 2 inhibitable pathway independent of the canonical initiator caspase , caspase 9 , and its adaptor , Apaf 1 . ^^^ Here we report that mast cells lacking caspase 9 or Apaf 1 are refractory to apoptosis after cytotoxic insults but still lose effector function and ability to proliferate . ^^^ In response to cytokine deprivation or DNA damage , fetal liver derived mast cells lacking Apaf 1 or caspase 9 failed to undergo apoptosis . ^^^ Furthermore , mast cells lacking Apaf 1 or caspase 9 had no survival advantage over wild type counterparts in vivo . ^^^
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Strikingly , the overall packing arrangement between the two DEDs of MC 159 resembles that between the caspase recruitment domains of Apaf 1 and caspase 9 . ^^^
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It is assumed that the Apaf 1 caspase 9 apoptosome processes caspase 7 in an analogous manner to that described for caspase 3 . ^^^
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Furthermore , orthologues of the apoptosome components , Ark ( Apaf 1 ) and Dronc ( caspase 9 ) , are also required for the proper removal of bulk cytoplasm during spermatogenesis . ^^^
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To clarify the controversy concerning whether the cell death of motor neurons in ALS is apoptosis , we investigated the expression of Apaf 1 and caspase 9 mRNA in spinal cord tissue obained at autopsy from patients with ALS and controls using RT PCR ; the presence of in situ nuclear DNA fragmentation in motor neurons by the TdT mediated dUTP biotin nick end labeling ( TUNEL ) method ; and immunocytochemical localization of Apaf 1 and caspase 3 , which are known as promotors of apoptotic processes . ^^^ Although Apaf 1 and caspase 9 mRNAs levels were increased in ALS , Apaf 1 immunoreactivity ( IR ) showed no significant difference between ALS and the control , and caspase 3 IR was not observed in ALS motoneurons , casting doubt on the notion that motor neurons in ALS undergo death by the classic apoptotic pathway . ^^^
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RESULTS : Hsp 70 overexpression reduced cytosolic translocation of cytochrome c without affecting the levels of Apaf 1 and pro caspase 9 24 hours after H / I . ^^^ Reduced caspase 9 cleavage occurred in Hsp 70 Tg mice compared with Wt littermates 24 hours after H / I and correlated with increased binding of Hsp 70 and Apaf 1 . ^^^ CONCLUSIONS : Our results suggest that the extrinsic and intrinsic apoptotic pathways mediate the neuroprotective effects of Hsp 70 overexpression in neonatal H / I , specifically by upregulating FLIP and sequestering Apaf 1 , leading to reduced cleavage of caspase 8 and caspase 9 . . ^^^
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This sensitivity , not observed in other cancers , resulted from enhanced recruitment of caspase 9 to the Apaf 1 caspase recruitment domain . ^^^
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The apoptosis effector molecules Bax and Bak , Apaf 1 , and caspase 9 were shown to be downstream of p 53 in both pathways . ^^^
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Apoptosome ( a multi protein complex consisting of cytochrome c , Apaf 1 , caspase 9 , and ATP ) formation was confirmed by immunoprecipitation using cytochrome c antibody . ^^^
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In muscle biopsy specimens from 14 patients with a dystrophinopathy ( 10 patients with DMD , two with Becker MD , two DMD carriers ) , expression of APAF 1 and caspase 9 , upstream members of the apoptotic protease cascade , as well as of the downstream executioners caspase 2 , 6 and 7 , were studied by immunohistochemistry and Western blots . ^^^ However , lacking coexpression of APAF 1 suggests the existence of other pathways of caspase 9 activation than through the `` apoptosome ' ' in dystrophinopathies . . ^^^
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The Apaf 1 protein is essential for cytochrome c mediated caspase 9 activation in the intrinsic mammalian pathway of apoptosis . ^^^ In Drosophila melanogaster , the only Apaf 1 / CED 4 homologue , ARK , is required for the activation of the caspase 9 / CED 3 like caspase DRONC . ^^^
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Examples of prominent CARD proteins are caspase 9 and Apaf 1 , which are involved in the intrinsic death pathway ; BCL 10 and CARD 11 , which mediate antigen receptor induced NF kappaB activation ; and receptor interacting protein ( RIP ) like interacting caspase like apoptosis regulatory protein kinase ( RICK ) and the nucleotide binding oligomerization domain ( NOD ) proteins , which induce NF kappaB activation in response to intracellular bacterial peptidoglycan . ^^^
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Many proapoptotic stimuli trigger cytochrome c release from mitochondria , promoting the formation of a complex between Apaf 1 and caspase 9 in a caspase activating structure known as the apoptosome . ^^^
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Nucling is a novel type of apoptosis associated molecule , essential for cytochrome c , apoptosis protease activating factor 1 ( Apaf 1 ) , pro caspase 9 apoptosome induction and caspase 9 activation following pro apoptotic stress . ^^^
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LBH 589 favored apoptosome formation by inducing cytochrome c release , Apaf 1 up regulation , and caspase 9 cleavage . ^^^
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Instead , decrease in the content of Apaf 1 and caspase 3 and some degradation of caspase 9 during brain ageing were observed . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
After cytochrome c is released into the cytosol from the mitochondria , it binds to Apaf 1 and ATP , which then activate caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Released cytochrome c interacts with apoptotic protease activating factor 1 and caspase 9 , both of which play important roles in the cytochrome c dependent mitochondrial pathway of apoptosis by activating caspase 3 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Moreover , the membrane potential ( deltapsi ( m ) ) was affected , and translocation of cytochrome c to the cytosol , overexpression of apoptotic protease activating factor 1 and a significant increase of caspase 9 activity were demonstrated , indicating that the apoptosome is formed . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Once released into the cytosol , cytochrome c binds to its adaptor molecule , apoptotic protease activating factor 1 , which oligomerizes and then activates pro caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Once released , cytochrome c cooperates with apoptotic protease activating factor 1 and deoxyadenosine triphosphate in caspase 9 activation and initiation of the apoptotic protease cascade . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
This was accompanied by increase in ( a ) protein expression of cytochrome c and apoptotic protease activating factor 1 and ( b ) activity and protein expression of caspase 3 , caspase 7 , caspase 8 , and caspase 9 . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
We found that the expression of mitochondrial apoptosis related genes ( Bcl 2 associated protein 10 , BAX ; apoptotic protease activating factor 1 , Apaf 1 ; Caspase 9 and serine / threonine protein kinase , PKB ) is elevated in Trichinella spiralis infected muscles during encapsulation . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The cells were mock , transiently , or stably transfected with genes for Triacsin c resistant ACSL 5 , dominant negative caspase 9 , or apoptotic protease activating factor 1 knockdown . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
The apoptotic protease activating factor 1 , an essential protein conserved in all three species , is responsible for the activation of the initiator caspase 9 in mammalian cells . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
Furthermore , there is no apoptosis in mutant retinal tissues for the Drosophila homologues of apoptotic protease activating factor 1 ( Ark ) and caspase 9 ( Dronc ) . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
CED 4 ) and with caspase 9 , that initiates the proteolitic cascade ( 1 , 2 ) . ^^^
Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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Interacting proteins: O14727 and P55211 Pubmed SVM Score :0.0
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