Melanoma Molecular Maps Projects



Title: IAP proteins, BH3 only proteins & apoptosis
Legend: The inhibitor of apoptosis (IAP) family of proteins (i.e. Survivin [BIRC5], Livin [BIRC7], c-IAP1 [BIRC2], c-IAP2 [BIRC3], XIAP [BIRC4], Apollon [BIRC6], NAIP [BIRC1], ILP2) protects cells from self-execution by blocking the caspase-mediated apoptosis. IAP bind to and inhibit activated caspases through their BIR (baculovirus IAP repeat) domains. Some IAP (e.g. Livin, XIAP, c-IAP1, c-IAP2) also contain a RING domain that has E3 ubiquitin ligase activity and promotes the degradation of SMAC (DIABLO) through ubiquitination. IAP (e.g. Survivin) are often overexpressed in tumors, including melanoma, which has prompted the development of IAP inhibitors (e.g. XIAP antisense oligonucleotide, Survivin small molecule inhibitor YM155) [1]. Since SMAC promotes apoptosis by inhibiting IAP-caspase interactions, the development of SMAC mimetics is underway as a potential anticancer approach [2]. The Bcl-2 family of proteins is characterized by the BH (Bcl-2 homology) domains (BH1 to BH4) and includes both pro-apoptotic (effectors: Bak, Bax; BH3 only proteins: Bid, Bad, Bim, Noxa, Puma, Bik, Bmf, Hrk) and anti-apoptotic members (Bcl-2, Bcl-XL, Bcl-W, MCL1) [3]. An important feature of the Bcl-2 family is that its members are capable of dimerizing with themselves or with other members of the family. Bak and Bax can oligomerize and cause mitochondrial outer membrane permeabilization, which leads to the release of pro-apoptotic factors SMAC, cytochrome-C (which forms the apoptosome along with APAF1) and Endo-G (a DNase). Bcl-2 pro-apoptotic members (e.g. Bcl-2) are often overexpressed in tumors (including melanoma), which has led to the development of their inhibitors (e.g. Bcl-2 antisense oligonucleotide, BH3 mimetics) [4]. REFERENCES: [1] Altieri DC, Nat Rev Cancer 2008, 8:61-70. [2] Bank A et al, Cancer Res 2008, 68:276-84. [3] Youle RJ et al, Nat Rev Mol Cell Biol 2008, 9:47-59. [4] Ralph SJ et al, Recent Patents Anticancer Drug Discov 2006, 1:327-46. Figure #46
Author: The MMMP Team (updated: February 2008)

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