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HGNC Approved Gene Symbol: BIRC3
Cytogenetic location: 11q22.2 Genomic coordinates (GRCh38): 11:102,317,484-102,339,403 (from NCBI)
Baculovirus inhibitors of apoptosis (IAPs) act in insect cells to prevent cell death. Uren et al. (1996) isolated cDNAs encoding 3 human IAP homologs, which they designated MIHC (mammalian IAP homolog C), MIHB (BIRC2; 601712), and MIHA (XIAP; 300079). All 3 predicted proteins contain 3 BIR (baculovirus IAP repeat) domains in the N-terminal region and a single RING finger domain close to the C terminus. MIHC shares 73% and 43% identity with MIHB and MIHA, respectively.
Independently, Liston et al. (1996) cloned cDNAs encoding BIRC3, which they called HIAP1, BIRC2, which they called HIAP2, and XIAP. By Northern blot analysis, Liston et al. (1996) found that HIAP1 is expressed as a 6.5-kb mRNA in fetal lung and kidney and in adult lymphoid tissues.
Uren et al. (1996) found that unlike MIHA and MIHB, MIHC did not inhibit apoptosis caused by ICE (147678) overexpression. However, Liston et al. (1996) determined that expression of all 3 human IAPs in mammalian cells inhibited serum deprivation-induced apoptosis and apoptosis triggered by treatment with menadione, a potent inducer of free radicals. Uren et al. (1996) reported that both MIHB and MIHC bound to the tumor necrosis factor receptor-associated factors TRAF1 (601711) and TRAF2 (601895) in yeast 2-hybrid assays, suggesting that IAP proteins that inhibit apoptosis may do so by regulating signals required for activation of ICE-like proteases.
Dai et al. (2003) used restriction landmark genomic scanning (RLGS) to identify novel amplified sequences in primary lung carcinomas and lung cancer cell lines. Enhanced RLGS fragments indicative of gene amplification were observed in tumors and cell lines of both nonsmall cell lung cancer (211980) and small cell lung cancer (182280). The authors identified a novel amplicon on chromosome 11q22 which was refined to 0.92 Mb in 1 patient sample. Immunohistochemistry and Western blot analysis identified BIRC2 (601712) and BIRC3 as potential oncogenes in this region, since both are overexpressed in multiple lung cancers with or without higher copy numbers.
Using differential display, Horrevoets et al. (1999) found that cytokines induced expression of HIAP1 in cultured human umbilical vein endothelial cells. HIAP1 was an early response gene, with expression peaking between 1.5 and 3 hours. TNF-alpha (191160), a proapoptotic protein, also induced HIAP1 expression. In situ hybridization detected HIAP1 in endothelial cells of atherosclerotic aorta and iliac arteries, coinciding with MCP1 (CCL2; 158105) expression, but not in normal arteries or arteries lacking monocyte/macrophage infiltrates.
Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Matsuzawa et al. (2008) reported that, upon ligation, CD40 (109535) formed a complex containing adaptor molecules TRAF2 and TRAF3 (601896), ubiquitin-conjugating enzyme UBC13 (UBE2N; 603679), CIAP1 and CIAP2, IKK-gamma (IKBKG; 300248), and MEKK1 (MAP3K1; 600982). TRAF2, UBC13, and IKK-gamma were required for complex assembly and activation of MEKK1 and MAP kinase cascades. However, the kinases were not activated unless the complex was translocated from the membrane to the cytosol upon CIAP1/CIAP2-induced degradation of TRAF3. Matsuzawa et al. (2008) proposed that this 2-stage signaling mechanism may apply to other innate immune receptors and may account for spatial and temporal separation of MAPK and IKK signaling.
Rosebeck et al. (2011) demonstrated that the API2/MALT1 (604860) fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-kappa-B-inducing kinase (NIK; 604655) at arginine-325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappa-B (see 164011) signaling, enhanced B-cell adhesion, and apoptosis resistance. Rosebeck et al. (2011) concluded that their study revealed the gain-of-function proteolytic activity of a fusion oncoprotein and highlighted the importance of the noncanonical NF-kappa-B pathway in B lymphoproliferative disease.
By analysis of a somatic cell hybrid panel, Liston et al. (1996) mapped the BIRC3 gene to chromosome 11. Rajcan-Separovic et al. (1996) used fluorescence in situ hybridization to map the BIRC3 gene to the boundary of chromosome 11q22 and 11q23. Since the BIRC2 gene is also localized to this region, the authors speculated that these genes arose by tandem duplication.
In mice lacking Birc2, Birc3, or Ripk2 (603455), or HT29 cells lacking Birc2 or Birc3 by RNAi depletion, Bertrand et al. (2009) showed that Birc2 and Birc3 are required for ubiquitination of Ripk2 and that these molecules are required for Ripk2-dependent activation of Mapk and Nfkb signaling pathways in response to Nod1 (605980) and Nod2 (605956) agonists. Cytokine and chemokine production was also reduced in macrophages from Birc2-null and Birc3-null mice. The reduced inflammatory response also resulted in resistance to peritonitis induction. Dextran sulfate sodium-induced colitis was not prevented by muramyl dipeptide Nod2 activation in mice with Ripk2 and Birc3 deficiency. Bertrand et al. (2009) concluded that cellular IAPs are key regulators of NOD innate immunity signaling.
Bertrand, M. J. M., Doiron, K., Labbe, K., Korneluk, R. G., Barker, P. A., Saleh, M. Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30: 789-801, 2009. [PubMed: 19464198] [Full Text: https://doi.org/10.1016/j.immuni.2009.04.011]
Dai, Z., Zhu, W.-G., Morrison, C. D., Brena, R. M., Smiraglia, D. J., Raval, A., Wu, Y.-Z., Rush, L. J., Ross, P., Molina, J. R., Otterson, G. A., Plass, C. A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes. Hum. Molec. Genet. 12: 791-801, 2003. [PubMed: 12651874] [Full Text: https://doi.org/10.1093/hmg/ddg083]
Horrevoets, A. J. G., Fontijn, R. D., van Zonneveld, A. J., de Vries, C. J. M., ten Cate, J. W., Pannekoek, H. Vascular endothelial genes that are responsive to tumor necrosis factor-alpha in vitro are expressed in atherosclerotic lesions, including inhibitor of apoptosis protein-1, stannin, and two novel genes. Blood 93: 3418-3431, 1999. [PubMed: 10233894]
Liston, P., Roy, N., Tamai, K., Lefebvre, C., Baird, S., Cherton-Horvat, G., Farahani, R., McLean, M., Ikeda, J.-E., MacKenzie, A., Korneluk, R. G. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379: 349-353, 1996. [PubMed: 8552191] [Full Text: https://doi.org/10.1038/379349a0]
Matsuzawa, A., Tseng, P.-H., Vallabhapurapu, S., Luo, J.-L., Zhang, W., Wang, H., Vignali, D. A. A., Gallagher, E., Karin, M. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 321: 663-668, 2008. Note: Erratum: Science 322: 375 only, 2008. [PubMed: 18635759] [Full Text: https://doi.org/10.1126/science.1157340]
Rajcan-Separovic, E., Liston, P., Lefebvre, C,, Korneluk, R. G. Assignment of human inhibitor of apoptosis protein (IAP) genes xiap, hiap-1, and hiap-2 to chromosomes Xq25 and 11q22-q23 by fluorescence in situ hybridization. Genomics 37: 404-406, 1996. [PubMed: 8938457] [Full Text: https://doi.org/10.1006/geno.1996.0579]
Rosebeck, S., Madden, L., Jin, X., Gu, S., Apel, I. J., Appert, A., Hamoudi, R. A., Noels, H., Sagaert, X., Van Loo, P., Baens, M., Du, M.-Q., Lucas, P. C., McAllister-Lucas, L. M. Cleavage of NIK by the API1-MALT1 fusion oncoprotein leads to noncanonical NF-kappa-B activation. Science 331: 468-472, 2011. Note: Erratum: Science 332, 421 only, 2011. [PubMed: 21273489] [Full Text: https://doi.org/10.1126/science.1198946]
Uren, A. G., Pakusch, M., Hawkins, C. J., Puls, K. L., Vaux, D. L. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc. Nat. Acad. Sci. 93: 4974-4978, 1996. [PubMed: 8643514] [Full Text: https://doi.org/10.1073/pnas.93.10.4974]