%0 Journal Article
%T The Opposing Roles of Cellular Inhibitor of Apoptosis Proteins in Cancer
%A R. Lau
%A M. A. C. Pratt
%J ISRN Oncology
%D 2012
%R 10.5402/2012/928120
%X 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-¦ĘB 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-¦ĘB activation. 2. Regulation of NF-kB by cIAPs Activation of NF-¦ĘB signaling regulates a large number of genes involved in a wide range of
%U http://www.hindawi.com/journals/isrn.oncology/2012/928120/