Alternative titles; symbols
HGNC Approved Gene Symbol: BIRC2
Cytogenetic location: 11q22.2 Genomic coordinates (GRCh38): 11:102,347,214-102,378,670 (from NCBI)
Tumor necrosis factor (TNF; 191160) is a cytokine that mediates pleiotropic inflammatory and immunoregulatory responses via 2 distinct cell surface receptors of approximately 55 kD (TNFR1; 191190) and 75 kD (see TNFR2; 191191). Several TNF receptor-associated factors, or TRAFs (see 601711), have been identified. Rothe et al. (1995) identified and cloned 2 human proteins that interact with TNFR2. These proteins, designated cIAP1 and cIAP2 (BIRC3; 601721) by them, are members of the inhibitor-of-apoptosis protein family (IAP; see 300079). The cIAPs do not directly contact TNFR2, but associate with TRAF1 and TRAF2.
Liston et al. (1996) and Uren et al. (1996) also isolated cDNAs encoding cIAP1, which they designated HIAP2 and MIHB (mammalian IAP homolog B), respectively. By Northern blot analysis, Liston et al. (1996) found that HIAP2 is expressed as a 4.5-kb mRNA in many fetal and adult tissues, with the highest expression in adult skeletal muscle and pancreas. They reported that, like cIAP2 and XIAP (300079), the predicted HIAP2 protein contains 3 BIR (baculovirus IAP repeat) domains in the N-terminal region and a single RING finger domain close to the C-terminus. HIAP2 shares 72% and 42% identity with cIAP2 and XIAP, respectively. Expression of HIAP2 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) determined that expression of MIHB in mammalian cells significantly reduced apoptosis mediated by ICE (147678). They stated that the ability of MIHB to bind TRAFs suggested that MIHB may inhibit apoptosis by regulating signals required for activation of ICE-like proteases.
To determine why proteasome inhibitors prevent thymocyte death, Yang et al. (2000) examined whether proteasomes degrade antiapoptotic molecules in cells induced to undergo apoptosis. The cIAP1 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wildtype cIAP1, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wildtype XIAP. Yang et al. (2000) concluded that autoubiquitination and degradation of IAPs may be a key event in the apoptotic program.
Using Jurkat T cells, which express TNFR1 but little TNFR2, and Jurkat cells stably transfected with TNFR2, Li et al. (2002) confirmed that TNF stimulation, or stimulation with a TNFR2, but not TNFR1, agonist, causes a loss of TRAF2 (601895) in the TNFR2-expressing cells, but not the parental cell line, through a ubiquitination- and proteasome-dependent process. Binding analysis indicated that TRAF2 interacts with CIAP1 and CIAP2, which possess E3 ubiquitin ligase (e.g., UBE3A, 601623) activity. Ubiquitination assays and SDS-PAGE analysis showed that in the presence of an E2-conjugating enzyme (e.g., UBCH7, 603721), CIAP1, but not CIAP2, induces TRAF2 ubiquitination outside of its RING domain. Both CIAPs bind but neither ubiquitinates TRAF1 (601711). CIAP1 expression fails to protect TNFR2-expressing cells from TNF-induced apoptosis, whereas an E3-inactive CIAP1 mutant and wildtype CIAP2 do protect cells from TRAF2 downregulation and cause a delay in cell death. Li et al. (2002) concluded that TNFR2 stimulation causes the ubiquitination of TRAF2 by CIAP1, which can play a proapoptotic role in TNF signaling.
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 and BIRC3 as potential oncogenes in this region, since both are overexpressed in multiple lung cancers with or without higher copy numbers.
Jin et al. (2003) found that CIAP1 was involved in the p53 (TP53; 191170)-dependent response to apoptotic stimuli. In both primary mouse thymocytes and HeLa cells, the mitochondrial serine protease HTRA2 (606441) cleaved CIAP1. HTRA2 expression was induced by p53, and cleavage of CIAP1 by HTRA2 was required to relieve caspase inhibition and activate apoptosis.
By genomewide analysis of tumors in a mouse model of hepatocellular carcinoma (114550) initiated from progenitor cells harboring defined cancer-predisposing lesions, Zender et al. (2006) identified a recurrent amplification at mouse chromosome 9qA1. Genomewide analysis of human tumors revealed amplification of chromosome 11q22, a region syntenic to mouse chromosome 9qA1, in 2 of 48 hepatocellular carcinomas, in 4 of 53 esophageal cancers (133239), and in an ovarian cancer (167000). Expression analysis of genes located in the human and mouse amplicons showed elevated expression of CIAP1 and YAP (YAP1; 606608) mRNA and protein in all human and mouse amplicon-containing hepatocellular carcinomas examined. Using the mouse model, Zender et al. (2006) showed that both Ciap1 and Yap exhibited oncogenic properties and were required to sustain rapid tumor growth in the genetic context of their amplification. Furthermore, Ciap1 and Yap cooperated to promote tumorigenesis. Zender et al. (2006) concluded that CIAP1 and YAP can act independently as oncogenes and can synergize in transforming hepatoblasts and promoting tumorigenesis by virtue of their coamplification at the same genomic locus.
Integrity of the blood vessel wall is essential for vascular homeostasis and organ function. The dynamic balance between endothelial cell survival and apoptosis contributes to this integrity during vascular development and pathologic angiogenesis. Santoro et al. (2007) showed that Birc2 is essential for maintaining endothelial cell survival and blood vessel homeostasis during vascular development. Using a forward-genetic approach, they identified a zebrafish null mutant for birc2, which showed severe hemorrhage and vascular regression due to defects in endothelial cell integrity and apoptosis. Using genetic and molecular approaches, they showed that Birc2 positively regulates the formation of the TNF receptor complex 1 in endothelial cells, thereby promoting NF-kappa-B activation and maintaining vessel integrity and stabilization. The findings identified Birc2 and TNF signaling components as critical regulators of vascular integrity and endothelial cell survival, thereby providing an additional target pathway for the control of angiogenesis and blood vessel homeostasis during embryogenesis, regeneration, and tumorigenesis.
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.
Shembade et al. (2010) showed that A20 (191163) inhibits the E3 ligase activities of TRAF6 (602355), TRAF2, and cIAP1 by antagonizing interactions with E2 ubiquitin-conjugating enzymes UBC13 (603679) and UBCH5C (602963). A20, together with the regulatory molecule TAX1BP1 (605326), interacted with UBC13 and UBCH5C and triggered their ubiquitination and proteasome-dependent degradation. These findings suggested a mechanism of A20 action in the inhibition of inflammatory signaling pathways.
By analysis of a somatic cell hybrid panel, Liston et al. (1996) mapped the BIRC2 (HIAP2) gene to chromosome 11. Rajcan-Separovic et al. (1996) used fluorescence in situ hybridization to map the BIRC2 gene to the boundary of 11q22 and 11q23. Since BIRC3 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 in 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 (164011) 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 inhibitors of apoptosis (cIAPs) 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]
Jin, S., Kalkum, M., Overholtzer, M., Stoffel, A., Chait, B. T., Levine, A. J. CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals. Genes Dev. 17: 359-367, 2003. [PubMed: 12569127] [Full Text: https://doi.org/10.1101/gad.1047003]
Li, X., Yang, Y., Ashwell, J. D. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature 416: 345-349, 2002. [PubMed: 11907583] [Full Text: https://doi.org/10.1038/416345a]
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]
Rothe, M., Pan, M.-G., Henzel, W. J., Ayres, T. M., Goeddel, D. V. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83: 1243-1252, 1995. [PubMed: 8548810] [Full Text: https://doi.org/10.1016/0092-8674(95)90149-3]
Santoro, M. M., Samuel, T., Mitchell, T., Reed, J. C., Stainier, D. Y. R. Birc2 (cIap1) regulates endothelial cell integrity and blood vessel homeostasis. Nature Genet. 39: 1397-1402, 2007. [PubMed: 17934460] [Full Text: https://doi.org/10.1038/ng.2007.8]
Shembade, N., Ma, A., Harhaj, E. W. Inhibition of NF-kappa-B signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327: 1135-1139, 2010. [PubMed: 20185725] [Full Text: https://doi.org/10.1126/science.1182364]
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]
Yang, Y., Fang, S., Jensen, J. P., Weissman, A. M., Ashwell, J. D. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288: 874-877, 2000. [PubMed: 10797013] [Full Text: https://doi.org/10.1126/science.288.5467.874]
Zender, L., Spector, M. S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.-T., Luk, J. M., Wigler, M., Hannon, G. J., Mu, D., Lucito, R., Powers, S., Lowe, S. W. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125: 1253-1267, 2006. [PubMed: 16814713] [Full Text: https://doi.org/10.1016/j.cell.2006.05.030]