The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

XIAP  -  X-linked inhibitor of apoptosis, E3...

Homo sapiens

Synonyms: API3, BIRC4, Baculoviral IAP repeat-containing protein 4, E3 ubiquitin-protein ligase XIAP, IAP-3, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of BIRC4

  • XIAP is structurally characterized by three baculovirus IAP repeat (BIR) domains that mediate binding to and inhibition of caspases and a RING domain that confers ubiquitin ligase activity [1].
  • The Akt-XIAP pathway may be a potential molecular target for regulating colorectal cancer progression [2].
  • XIAP mRNA level in primary colorectal cancer was significantly higher than that in colorectal normal mucosa (P = 0.01); liver metastases was significantly higher than primary colorectal cancer tumors (P = 0.04); and primary colorectal cancer N1/N2 cases were significantly higher than N0 cases (P = 0.008) [2].
  • Acquired TRAIL resistance in human breast cancer cells are caused by the sustained cFLIP(L) and XIAP protein levels and ERK activation [3].
  • Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma [4].

Psychiatry related information on BIRC4


High impact information on BIRC4

  • Consistent with this finding, binding of the caspase-9 linker peptide and Smac to the BIR3 domain of XIAP is mutually exclusive, suggesting that Smac potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3 [6].
  • Supporting this observation, point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9, or deletion of the linker peptide, prevented caspase-9 association with XIAP and its concomitant inhibition [6].
  • X-linked IAP is a direct inhibitor of cell-death proteases [7].
  • One cellular inhibitor of apoptosis, XIAP, has emerged as a crucial regulator of caspases, and is itself subject to complex negative regulation [8].
  • X-linked inhibitor of apoptosis (XIAP), known primarily for its caspase inhibitory properties, has recently been shown to interact with and regulate the levels of COMMD1, a protein associated with a form of canine copper toxicosis [9].

Chemical compound and disease context of BIRC4


Biological context of BIRC4


Anatomical context of BIRC4


Associations of BIRC4 with chemical compounds

  • Here, using glutathione S-transferase pulldown and caspase activity assay, we show that Smac is ineffective in relieving either caspase-7 or caspase-9 inhibition by XIAP domain fragments [20].
  • Interestingly, the expression of IAP-2, XIAP, and survivin gradually increased with the extent of cisplatin-resistance [16].
  • Cinnamaldehyde also upregulated the expression of pro-apoptotic protein (Bax) and down-regulated the levels of anti-apoptotic proteins, such as Bcl-2 and the inhibitor of apoptosis protein family (X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein (cIAP)-1 and cIAP-2) [21].
  • The expression of apoptotic inhibitors (XIAP, cIAP-1, cIAP-2) and anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) proteins was affected by vitamin E pretreatment [21].
  • The internal ribosome entry site-mediated translation of antiapoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins C1 and C2 [22].

Physical interactions of BIRC4

  • The cIAP BIR domains can be converted to tight binding caspase inhibitors by substituting these critical residues with XIAP residues [23].
  • Cleaved SMAC binds X-IAP and antagonizes its anti-apoptotic activity [24].
  • In vivo co-precipitation experiments show that both ILPIP and XIAP interact with TAK1 and tumor necrosis factor receptor-associated factor 6 [25].
  • Here we have isolated the protein XIAP-associated factor 1 (XAF1) on the basis of its ability to bind XIAP, a member of the IAP family [26].
  • The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif [27].

Regulatory relationships of BIRC4

  • The inhibitory activity of X-IAP is regulated by SMAC, a protein that is processed to its active form upon receipt of a death stimulus [24].
  • The transfection of siRNA targeted for XIAP also enhanced X-ray sensitivity even more for TP53 mutant cells compared to TP53 wild-type cells [28].
  • Expression of XAF1 triggers a redistribution of XIAP from the cytosol to the nucleus [26].
  • Injection of XIAP mRNA into dorsal blastomeres enhanced the ventralization of Xenopus embryos in a TAB1-TAK1-dependent manner [29].
  • Taken together, our data suggested that Cyr61 plays an important role in resistance to chemotherapeutic agent-induced apoptosis in human breast cancer MCF-7 cells by a mechanism involving the activation of the integrins/NF-kappaB/XIAP signaling pathway [30].

Other interactions of BIRC4

  • Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain [31].
  • The dramatic potentiation of CDK inhibitor-induced apoptosis by LY was accompanied by diminished Bad phosphorylation, induction of Bcl-2 cleavage, and down-regulation of X-linked IAP (XIAP) and Mcl-1 [32].
  • Interestingly, and in contrast to the X-chromosome-linked inhibitor of apoptosis protein (XIAP), NAIP-mediated inhibition of caspase-9 was not countered by a peptide containing an amino-terminal IAP binding motif (IBM) [33].
  • Unlike XAF1, XIAP expression exhibited no detectable alteration in cancers [34].
  • This testis-specific transcript contains a putative open reading frame (ORF) that is homologous to the carboxy-terminal end of BIRC4; overexpression of this ORF shows protective effects against BAX-induced apoptosis [15].

Analytical, diagnostic and therapeutic context of BIRC4

  • Four bands cross-react with a BIRC4 coding region probe on a genomic Southern blot [15].
  • The role of HGF/C-Met pathway through Akt and XIAP was investigated by small interfering RNA (siRNA) and quantitative RT-PCR analysis of colorectal cancer lines [2].
  • When XIAP protein expression was evaluated by Western blot, we observed that the induction of apoptosis by PHA was associated with a parallel decrease of XIAP expression [17].
  • These experiments suggest that it may be the ratio between XAF1 and XIAP that confers the resistance of adult motoneurons to axotomy [35].
  • We used site-directed mutagenesis of BIR2 and its linker to determine the mechanism of executioner caspase inhibition by XIAP [36].


  1. Smac3, a novel Smac/DIABLO splicing variant, attenuates the stability and apoptosis-inhibiting activity of X-linked inhibitor of apoptosis protein. Fu, J., Jin, Y., Arend, L.J. J. Biol. Chem. (2003) [Pubmed]
  2. X-Linked inhibitor of apoptosis protein expression level in colorectal cancer is regulated by hepatocyte growth factor/C-met pathway via Akt signaling. Takeuchi, H., Kim, J., Fujimoto, A., Umetani, N., Mori, T., Bilchik, A., Turner, R., Tran, A., Kuo, C., Hoon, D.S. Clin. Cancer Res. (2005) [Pubmed]
  3. Acquired TRAIL resistance in human breast cancer cells are caused by the sustained cFLIP(L) and XIAP protein levels and ERK activation. Lee, T.J., Lee, J.T., Park, J.W., Kwon, T.K. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  4. Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma. Wagenknecht, B., Glaser, T., Naumann, U., Kügler, S., Isenmann, S., Bähr, M., Korneluk, R., Liston, P., Weller, M. Cell Death Differ. (1999) [Pubmed]
  5. Differential regulation of inhibitors of apoptosis proteins in Alzheimer's disease brains. Christie, L.A., Su, J.H., Tu, C.H., Dick, M.C., Zhou, J., Cotman, C.W. Neurobiol. Dis. (2007) [Pubmed]
  6. A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Srinivasula, S.M., Hegde, R., Saleh, A., Datta, P., Shiozaki, E., Chai, J., Lee, R.A., Robbins, P.D., Fernandes-Alnemri, T., Shi, Y., Alnemri, E.S. Nature (2001) [Pubmed]
  7. X-linked IAP is a direct inhibitor of cell-death proteases. Deveraux, Q.L., Takahashi, R., Salvesen, G.S., Reed, J.C. Nature (1997) [Pubmed]
  8. XIAP, the guardian angel. Holcik, M., Korneluk, R.G. Nat. Rev. Mol. Cell Biol. (2001) [Pubmed]
  9. XIAP Is a copper binding protein deregulated in Wilson's disease and other copper toxicosis disorders. Mufti, A.R., Burstein, E., Csomos, R.A., Graf, P.C., Wilkinson, J.C., Dick, R.D., Challa, M., Son, J.K., Bratton, S.B., Su, G.L., Brewer, G.J., Jakob, U., Duckett, C.S. Mol. Cell (2006) [Pubmed]
  10. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway sensitizes MDA-MB468 human breast cancer cells to cerulenin-induced apoptosis. Liu, X., Shi, Y., Giranda, V.L., Luo, Y. Mol. Cancer Ther. (2006) [Pubmed]
  11. Determination of cell survival by RING-mediated regulation of inhibitor of apoptosis (IAP) protein abundance. Silke, J., Kratina, T., Chu, D., Ekert, P.G., Day, C.L., Pakusch, M., Huang, D.C., Vaux, D.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. Roscovitine sensitizes glioma cells to TRAIL-mediated apoptosis by downregulation of survivin and XIAP. Kim, E.H., Kim, S.U., Shin, D.Y., Choi, K.S. Oncogene (2004) [Pubmed]
  13. Rottlerin sensitizes glioma cells to TRAIL-induced apoptosis by inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Kim, E.H., Kim, S.U., Choi, K.S. Oncogene (2005) [Pubmed]
  14. Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Kim, E.H., Kim, H.S., Kim, S.U., Noh, E.J., Lee, J.S., Choi, K.S. Oncogene (2005) [Pubmed]
  15. Genomic organization of the X-linked inhibitor of apoptosis and identification of a novel testis-specific transcript. Lagacé, M., Xuan, J.Y., Young, S.S., McRoberts, C., Maier, J., Rajcan-Separovic, E., Korneluk, R.G. Genomics (2001) [Pubmed]
  16. Expression of the inhibitors of apoptosis proteins in cisplatin-resistant prostate cancer cells. Nomura, T., Yamasaki, M., Nomura, Y., Mimata, H. Oncol. Rep. (2005) [Pubmed]
  17. Role of XIAP protein, a human member of the inhibitor of apoptosis (IAP) protein family, in phytohemagglutinin-induced apoptosis of human T cell lines. Vitté-Mony, I., Korneluk, R.G., Diaz-Mitoma, F. Apoptosis (1997) [Pubmed]
  18. Proteasome inhibition results in TRAIL sensitization of primary keratinocytes by removing the resistance-mediating block of effector caspase maturation. Leverkus, M., Sprick, M.R., Wachter, T., Mengling, T., Baumann, B., Serfling, E., Bröcker, E.B., Goebeler, M., Neumann, M., Walczak, H. Mol. Cell. Biol. (2003) [Pubmed]
  19. Oxidants inhibit ERK/MAPK and prevent its ability to delay neutrophil apoptosis downstream of mitochondrial changes and at the level of XIAP. Gardai, S.J., Whitlock, B.B., Xiao, Y.Q., Bratton, D.B., Henson, P.M. J. Biol. Chem. (2004) [Pubmed]
  20. Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by Smac. Huang, Y., Rich, R.L., Myszka, D.G., Wu, H. J. Biol. Chem. (2003) [Pubmed]
  21. Effects of vitamin E on the cinnamaldehyde-induced apoptotic mechanism in human PLC/PRF/5 cells. Wu, S.J., Ng, L.T., Lin, C.C. Clin. Exp. Pharmacol. Physiol. (2004) [Pubmed]
  22. The internal ribosome entry site-mediated translation of antiapoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins C1 and C2. Holcík, M., Gordon, B.W., Korneluk, R.G. Mol. Cell. Biol. (2003) [Pubmed]
  23. The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. Eckelman, B.P., Salvesen, G.S. J. Biol. Chem. (2006) [Pubmed]
  24. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). Vucic, D., Deshayes, K., Ackerly, H., Pisabarro, M.T., Kadkhodayan, S., Fairbrother, W.J., Dixit, V.M. J. Biol. Chem. (2002) [Pubmed]
  25. ILPIP, a novel anti-apoptotic protein that enhances XIAP-mediated activation of JNK1 and protection against apoptosis. Sanna, M.G., da Silva Correia, J., Luo, Y., Chuang, B., Paulson, L.M., Nguyen, B., Deveraux, Q.L., Ulevitch, R.J. J. Biol. Chem. (2002) [Pubmed]
  26. Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Liston, P., Fong, W.G., Kelly, N.L., Toji, S., Miyazaki, T., Conte, D., Tamai, K., Craig, C.G., McBurney, M.W., Korneluk, R.G. Nat. Cell Biol. (2001) [Pubmed]
  27. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. Martins, L.M., Iaccarino, I., Tenev, T., Gschmeissner, S., Totty, N.F., Lemoine, N.R., Savopoulos, J., Gray, C.W., Creasy, C.L., Dingwall, C., Downward, J. J. Biol. Chem. (2002) [Pubmed]
  28. siRNA targeting NBS1 or XIAP increases radiation sensitivity of human cancer cells independent of TP53 status. Ohnishi, K., Scuric, Z., Schiestl, R.H., Okamoto, N., Takahashi, A., Ohnishi, T. Radiat. Res. (2006) [Pubmed]
  29. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. Yamaguchi, K., Nagai, S., Ninomiya-Tsuji, J., Nishita, M., Tamai, K., Irie, K., Ueno, N., Nishida, E., Shibuya, H., Matsumoto, K. EMBO J. (1999) [Pubmed]
  30. Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF-kappaB-dependent XIAP up-regulation. Lin, M.T., Chang, C.C., Chen, S.T., Chang, H.L., Su, J.L., Chau, Y.P., Kuo, M.L. J. Biol. Chem. (2004) [Pubmed]
  31. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Liu, Z., Sun, C., Olejniczak, E.T., Meadows, R.P., Betz, S.F., Oost, T., Herrmann, J., Wu, J.C., Fesik, S.W. Nature (2000) [Pubmed]
  32. The lethal effects of pharmacological cyclin-dependent kinase inhibitors in human leukemia cells proceed through a phosphatidylinositol 3-kinase/Akt-dependent process. Yu, C., Rahmani, M., Dai, Y., Conrad, D., Krystal, G., Dent, P., Grant, S. Cancer Res. (2003) [Pubmed]
  33. Neuronal apoptosis-inhibitory protein does not interact with Smac and requires ATP to bind caspase-9. Davoodi, J., Lin, L., Kelly, J., Liston, P., MacKenzie, A.E. J. Biol. Chem. (2004) [Pubmed]
  34. Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas. Byun, D.S., Cho, K., Ryu, B.K., Lee, M.G., Kang, M.J., Kim, H.R., Chi, S.G. Cancer Res. (2003) [Pubmed]
  35. Motoneuron resistance to apoptotic cell death in vivo correlates with the ratio between X-linked inhibitor of apoptosis proteins (XIAPs) and its inhibitor, XIAP-associated factor 1. Perrelet, D., Perrin, F.E., Liston, P., Korneluk, R.G., MacKenzie, A., Ferrer-Alcon, M., Kato, A.C. J. Neurosci. (2004) [Pubmed]
  36. XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. Scott, F.L., Denault, J.B., Riedl, S.J., Shin, H., Renatus, M., Salvesen, G.S. EMBO J. (2005) [Pubmed]
WikiGenes - Universities