Cellular inhibitors of apoptosis proteins 1 and 2 (cIAP1/2) are members of the inhibitor of apoptosis protein (IAP) family that has been implicated in the pathology of human cancers due to their overexpression and function as blockers of cell death in various cancers. As a result, small molecule IAP antagonists have been developed and are currently under clinical evaluation for potential therapeutic use. In contrast, recent evidence has indicated a tumour-suppressing role for the cIAPs. Mutations in or loss of cIAPs have been identified as molecular lesions that contribute to constitutive activation of NF-κB in hematopoietic malignancies. These studies reveal a context-dependent role for the cIAPs wherein both their overexpression and loss may contribute to tumourigenesis. 1. Cellular Inhibitor of Apoptosis Proteins (cIAPs) The inhibitor of apoptosis proteins (IAPs) are potent suppressors of apoptosis and the human family is comprised of eight members: cellular IAP 1 (cIAP1), cellular IAP 2 (cIAP2), X-linked IAP (XIAP), neuronal apoptosis inhibitory protein (NAIP), melanoma IAP (ML-IAP), survivin, Apollon, and IAP like protein 2 (ILP2) [1]. All IAP proteins are characterized by the presence of one to three baculovirus IAP repeat (BIR) domains, which are zinc-binding regions of approximately 70 amino acids that mediate protein-protein interactions [2]. A number of IAPs also contain a RING (really interesting new gene) domain that confers ubiquitin protein ligase (E3) activity and are capable of auto-ubiquitination, as well as ubiquitination of proteins involved in apoptosis and signaling [3]. cIAP1 and cIAP2 can bind caspases, but do not directly inhibit them [4]. Instead, they exert their antiapoptotic effects through protein-protein interactions and by modulating the levels of other proteins through their function as ubiquitin ligases. Firstly, cIAP1/2 can bind to Smac and sequester it from XIAP, allowing XIAP to inhibit caspases and suppress apoptosis [5]. Furthermore, the cIAPs can target caspases and Smac for degradation by mediating their ubiquitination [5, 6]. The ubiquitin ligase activity of the cIAPs is conferred by the presence of the RING domain in their carboxy terminus and their substrates include themselves and proteins involved in signaling [7], including multiple substrates in the tumour necrosis factor receptor (TNFR) complex [8, 9]. This function imparts a role for cIAPs in the regulation of NF-κB activation. 2. Regulation of NF-kB by cIAPs Activation of NF-κB signaling regulates a large number of genes involved in a wide range of
References
[1]
G. S. Salvesen and C. S. Duckett, “IAP proteins: blocking the road to death's door,” Nature Reviews Molecular Cell Biology, vol. 3, no. 6, pp. 401–410, 2002.
[2]
M. G. Hinds, R. S. Norton, D. L. Vaux, and C. L. Day, “Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat,” Nature Structural Biology, vol. 6, no. 7, pp. 648–651, 1999.
[3]
S. M. Srinivasula and J. D. Ashwell, “IAPs: what's in a name?” Molecular Cell, vol. 30, no. 2, pp. 123–135, 2008.
[4]
B. P. Eckelman and G. S. Salvesen, “The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases,” Journal of Biological Chemistry, vol. 281, no. 6, pp. 3254–3260, 2006.
[5]
S. Hu and X. Yang, “Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO,” Journal of Biological Chemistry, vol. 278, no. 12, pp. 10055–10060, 2003.
[6]
Y. E. Choi, M. Butterworth, S. Malladi, C. S. Duckett, G. M. Cohen, and S. B. Bratton, “The E3 ubiquitin ligase cIAP1 binds and ubiquitinates caspase-3 and -7 via unique mechanisms at distinct steps in their processing,” Journal of Biological Chemistry, vol. 284, no. 19, pp. 12772–12782, 2009.
[7]
D. L. Vaux and J. Silke, “IAPs, RINGs and ubiquitylation,” Nature Reviews Molecular Cell Biology, vol. 6, no. 4, pp. 287–297, 2005.
[8]
M. J. M. Bertrand, S. Milutinovic, K. M. Dickson et al., “cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination,” Molecular Cell, vol. 30, no. 6, pp. 689–700, 2008.
[9]
T. Samuel, K. Welsh, T. Lober, S. H. Togo, J. M. Zapata, and J. C. Reed, “Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases,” Journal of Biological Chemistry, vol. 281, no. 2, pp. 1080–1090, 2006.
[10]
M. Karin, Y. Cao, F. R. Greten, and Z. W. Li, “NF-κB in cancer: from innocent bystander to major culprit,” Nature Reviews Cancer, vol. 2, no. 4, pp. 301–310, 2002.
[11]
M. Rothe, M. G. Pan, W. J. Henzel, T. M. Ayres, and D. V. Goeddel, “The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins,” Cell, vol. 83, no. 7, pp. 1243–1252, 1995.
[12]
H. Hsu, J. Xiong, and D. V. Goeddel, “The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation,” Cell, vol. 81, no. 4, pp. 495–504, 1995.
[13]
C. Wang, L. Deng, M. Hong, G. R. Akkaraju, J. I. Inoue, and Z. J. Chen, “TAK1 is a ubiquitin-dependent kinase of MKK and IKK,” Nature, vol. 412, no. 6844, pp. 346–351, 2001.
[14]
E. Varfolomeev, T. Goncharov, A. V. Fedorova et al., “c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor α (TNFα)-induced NF-κB activation,” Journal of Biological Chemistry, vol. 283, no. 36, pp. 24295–24299, 2008.
[15]
C. Y. Wang, M. W. Mayo, R. G. Korneluk, D. V. Goeddel, and A. S. Baldwin, “NF-？B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c- IAP2 to suppress caspase-8 activation,” Science, vol. 281, no. 5383, pp. 1680–1683, 1998.
[16]
M. Karin and A. Lin, “NF-κB at the crossroads of life and death,” Nature Immunology, vol. 3, no. 3, pp. 221–227, 2002.
[17]
G. Liao, M. Zhang, E. W. Harhaj, and S. C. Sun, “Regulation of the NF-κB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation,” Journal of Biological Chemistry, vol. 279, no. 25, pp. 26243–26250, 2004.
[18]
B. J. Zarnegar, Y. Wang, D. J. Mahoney et al., “Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK,” Nature Immunology, vol. 9, no. 12, pp. 1371–1378, 2008.
[19]
S. Vallabhapurapu, A. Matsuzawa, W. Z. Zhang et al., “Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-κB signaling,” Nature Immunology, vol. 9, no. 12, pp. 1364–1370, 2008.
[20]
C. M. Annunziata, R. E. Davis, Y. Demchenko et al., “Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma,” Cancer Cell, vol. 12, no. 2, pp. 115–130, 2007.
[21]
J. J. Keats, R. Fonseca, M. Chesi et al., “Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma,” Cancer Cell, vol. 12, no. 2, pp. 131–144, 2007.
[22]
Z. Liu, H. Li, X. Wu et al., “Detachment-induced upregulation of XIAP and cIAP2 delays anoikis of intestinal epithelial cells,” Oncogene, vol. 25, no. 59, pp. 7680–7690, 2006.
[23]
R. B. Hamanaka, E. Bobrovnikova-Marjon, X. Ji, S. A. Liebhaber, and J. A. Diehl, “PERK-dependent regulation of IAP translation during ER stress,” Oncogene, vol. 28, no. 6, pp. 910–920, 2009.
[24]
Z. L. Chu, T. A. McKinsey, L. Liu, J. J. Gentry, M. H. Malim, and D. W. Ballard, “Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-κB control,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 19, pp. 10057–10062, 1997.
[25]
S. Y. Hong, W. H. Yoon, J. H. Park, S. G. Kang, J. H. Ahn, and T. H. Lee, “Involvement of two NF-κB binding elements in tumor necrosis factor α-, CD40-, and Epstein-Barr virus latent membrane protein 1-mediated induction of the cellular inhibitor of apoptosis protein 2 gene,” Journal of Biological Chemistry, vol. 275, no. 24, pp. 18022–18028, 2000.
[26]
Z. Liu, H. Li, M. Derouet et al., “ras oncogene triggers up-regulation of cIAP2 and XIAP in intestinal epithelial cells: epidermal growth factor receptor-dependent and -independent mechanisms of ras-induced transformation,” Journal of Biological Chemistry, vol. 280, no. 45, pp. 37383–37392, 2005.
[27]
H. H. Wu, J. Y. Wu, Y. W. Cheng et al., “cIAP2 upregulated by E6 oncoprotein via epidermal growth factor receptor/phosphatidylinositol 3-kinase/AKT pathway confers resistance to cisplatin in human papillomavirus 16/18-infected lung cancer,” Clinical Cancer Research, vol. 16, no. 21, pp. 5200–5210, 2010.
[28]
C. W. Wright and C. S. Duckett, “Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function,” Journal of Clinical Investigation, vol. 115, no. 10, pp. 2673–2678, 2005.
[29]
Z. Dai, W. G. Zhu, C. D. Morrison et al., “A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes,” Human Molecular Genetics, vol. 12, no. 7, pp. 791–801, 2003.
[30]
E. C. LaCasse, D. J. Mahoney, H. H. Cheung, S. Plenchette, S. Baird, and R. G. Korneluk, “IAP-targeted therapies for cancer,” Oncogene, vol. 27, no. 48, pp. 6252–6275, 2008.
[31]
I. Imoto, Z. Q. Yang, A. Pimkhaokham et al., “Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas,” Cancer Research, vol. 61, no. 18, pp. 6629–6634, 2001.
[32]
T. Akagi, M. Motegi, A. Tamura et al., “A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue,” Oncogene, vol. 18, no. 42, pp. 5785–5794, 1999.
[33]
J. Dierlamm, M. Baens, I. Wlodarska et al., “The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa- associated lymphoid tissue lymphomas,” Blood, vol. 93, no. 11, pp. 3601–3609, 1999.
[34]
D. Vucic and W. J. Fairbrother, “The inhibitor of apoptosis proteins as therapeutic targets in cancer,” Clinical Cancer Research, vol. 13, no. 20, pp. 5995–6000, 2007.
[35]
E. Varfolomeev, J. W. Blankenship, S. M. Wayson et al., “IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB Activation, and TNFα-Dependent Apoptosis,” Cell, vol. 131, no. 4, pp. 669–681, 2007.
[36]
J. E. Vince, W. W. L. Wong, N. Khan et al., “IAP antagonists target cIAP1 to induce TNFα-dependent apoptosis,” Cell, vol. 131, no. 4, pp. 682–693, 2007.
[37]
S. L. Petersen, L. Wang, A. Yalcin-Chin et al., “Autocrine TNFα signaling renders human cancer cells susceptible to smac-mimetic-induced apoptosis,” Cancer Cell, vol. 12, no. 5, pp. 445–456, 2007.
[38]
D. J. Mahoney, H. H. Cheung, R. Lejmi Mrad et al., “Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, pp. 11778–11783, 2008.
[39]
L. Wang, F. Du, and X. Wang, “TNF-α induces two distinct caspase-8 activation pathways,” Cell, vol. 133, no. 4, pp. 693–703, 2008.
[40]
H. H. Cheung, D. J. Mahoney, E. C. LaCasse, and R. G. Korneluk, “Down-regulation of c-FLIP enhances death of cancer cells by Smac mimetic compound,” Cancer Research, vol. 69, no. 19, pp. 7729–7738, 2009.
[41]
D. Rossi, S. Deaglio, D. Dominguez-Sola, et al., “Alteration of BIRC3 and multiple other NF-kappaB pathway genes in splenic marginal zone lymphoma,” Blood, vol. 118, no. 18, pp. 4930–4934, 2011.
[42]
D. Rossi, M. Fangazio, S. Rasi, et al., “Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia,” Blood, vol. 119, no. 12, pp. 2854–2862, 2012.
[43]
V. Tergaonkar, M. Pando, O. Vafa, G. Wahl, and I. Verma, “p53 stabilization is decreased upon NFκB activation: a role for NFκB in acquisition of resistance to chemotherapy,” Cancer Cell, vol. 1, no. 5, pp. 493–503, 2002.
[44]
U. Siebenlist, K. Brown, and E. Claudio, “Control of lymphocyte development by nuclear factor-kB,” Nature Reviews Immunology, vol. 5, no. 6, pp. 435–445, 2005.
[45]
D. S. Bassères and A. S. Baldwin, “Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression,” Oncogene, vol. 25, no. 51, pp. 6817–6830, 2006.
