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. 2012:2012:928120.
doi: 10.5402/2012/928120. Epub 2012 Aug 9.

The opposing roles of cellular inhibitor of apoptosis proteins in cancer

R Lau  1 , M A C Pratt
Affiliations

The opposing roles of cellular inhibitor of apoptosis proteins in cancer

R Lau et al. ISRN Oncol. 2012.

Abstract

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.

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Figures

Figure 1
Figure 1
cIAP1/2 participates in positive and negative regulation of NF-κB. cIAP1/2 are recruited to an activated TNF receptor where they mediate K-63 polyubiquitination of RIP1. RIP1 subsequently activates the IKK complex, resulting in activation of canonical NF-κB complexes. In contrast, cIAP1/2 represses activation of canonical and noncanonical NF-κB signaling by ubiquitinating NIK, leading to its degradation. Mutation or loss of cIAP1/2 results in accumulation of NIK, resulting in activation of both canonical and noncanonical NF-κB. Activated NF-κB complexes promote the transcription of various growth and survival factors, such as IL6 (Interleukin 6) and BAFF (B-cell activating factor). cIAP, cellular inhibitor of apoptosis; IKK, IκB kinase; NIK, NF-κB inducing kinase; RIP, receptor interacting protein; TNF, tumour necrosis factor; TNFR, TNF receptor; TRAF, TNFR-associated factor; TRADD, TNFR-associated death domain.
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