Abstract
Defects in apoptosis regulation are one main cause of cancer development and may result from overexpression of anti-apoptotic proteins such as inhibitor of apoptosis proteins (IAPs). IAPs are cell death regulators that, among other functions, bind caspases, and interfere with apoptotic signaling via death receptors or intrinsic cell death pathways. All IAPs share one to three common structures, the so called baculovirus-IAP-repeat (BIR)-domains that allow them to bind caspases and other proteins. X-linked inhibitor of apoptosis protein (XIAP) is the most potent and best-defined anti-apoptotic IAP family member that directly neutralizes caspase-9 via its BIR3 domain and the effector caspases-3 and -7 via its BIR2 domain. A natural inhibitor of XIAP is SMAC/Diablo, which is released from mitochondria in apoptotic cells and displaces bound caspases from the BIR2/BIR3 domains of XIAP thereby reactivating cell death execution. The central apoptosis-inhibitory function of XIAP and its overexpression in many different types of advanced cancers have led to significant efforts to identify therapeutics that neutralize its anti-apoptotic effect. Most of these drugs are chemical derivatives of the N-terminal part of SMAC/Diablo. These “SMAC-mimetics” either specifically induce apoptosis in cancer cells or act as drug-sensitizers. Several “SMAC-mimetics” are currently tested by the pharmaceutical industry in Phase I and Phase II trials. In this review, we will discuss recent advances in understanding the function of IAPs in normal and malignant cells and focus on approaches to specifically neutralize XIAP in cancer cells.
Highlights
THE inhibitor of apoptosis proteins (IAPs) FAMILY – STRUCTURE AND FUNCTION OF IAPs Aggressive cancer cells develop due to an accumulation of genetic and epigenetic abnormalities, defects in the intracellular signal transduction pathways, in proliferation and migration regulation, and the apoptotic cell death machinery
X-linked inhibitor of apoptosis protein (XIAP), cIAP1/2, ILP2, and ML-IAP belong to the IAP-class 1 as they all contain a characteristical C-terminal RING domain that acts as an E3-ubiquitin ligase (Figure 1)
TRAF2 directly interacts with cIAP1 [25, 26] and cIAP2 [27, 28] via the BIR1 domain, which leads to Lys11/Lys63 linear ubiquitylation of RIP1 [29,30,31] thereby generating a platform for the recruitment of TGFβ-activated kinase 1 (TAK1)/TAK1 binding protein 1 (TAB1), which promotes activation of the IKKα/IKKβ/NEMO signaling complex and thereby NFκB [32]
Summary
THE IAP FAMILY – STRUCTURE AND FUNCTION OF IAPs Aggressive cancer cells develop due to an accumulation of genetic and epigenetic abnormalities, defects in the intracellular signal transduction pathways, in proliferation and migration regulation, and the apoptotic cell death machinery. XIAP as a therapeutical target in cancer therapy proteasomal degradation of bound proteins such as caspase-3 [4] or the mitochondrial XIAP-inhibitor SMAC/Diablo [5].
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