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XIAP: apoptotic brake and promising therapeutic target
M Holcik1, H Gibson, R G Korneluk
1AEgera Oncology, Inc., and Solange Gauthier-Karsh Molecular Genetics Laboratory, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON K1H 8L1, Canada.
Abstract:
The X-linked Inhibitor of Apoptosis, XIAP, is a key member of the newly discovered family of intrinsic inhibitors of apoptosis (IAP) proteins. IAPs block cell death both in vitro and in vivo by virtue of inhibition of distinct caspases. Although other proteins have been identified which inhibit upstream caspases, only the IAPs have been demonstrated to be endogenous repressors of the terminal caspase cascade. In turn, the caspase inhibiting activity of XIAP is negatively regulated by at least two XIAP-interacting proteins, XAF1 and Smac/DIABLO. In addition to the inhibition of caspases, recent discoveries from several laboratories suggest that XIAP is also involved in a number of other biologically significant cellular activities including modulation of receptor-mediated signal transduction and protein ubiquitination. XIAP is also translated by a rare cap-independent mechanism mediated by a specific sequence called IRES (for Internal Ribosome Entry Site) which is found in the XIAP 5(') UTR. XIAP protein is thus synthesized under various conditions of cellular stress such as serum starvation and low dose gamma-irradiation induced apoptosis, conditions that lead to the inhibition of cellular protein synthesis. The multiple biological activities of XIAP, its unique translational and post-translational control and the centrality of the caspase cascade make the control of XIAP expression an exceptionally promising molecular target for modulating apoptosis. Therapeutic benefits can be derived from both the suppression of inappropriate cell death such as in neurodegenerative disorders and ischemic injury or in the activation of latent cell death pathways such as in autoimmune disease and cancer where apoptosis induction is the desired outcome.
Insights
The X-linked Inhibitor of Apoptosis (XIAP) protein regulates cell death by inhibiting caspases. Controlling XIAP expression offers therapeutic potential for diseases involving cell death, such as cancer and neurodegeneration.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The X-linked Inhibitor of Apoptosis (XIAP) is a crucial intrinsic inhibitor of apoptosis (IAP) protein.
- IAPs, including XIAP, are endogenous repressors of the terminal caspase cascade, thereby blocking cell death.
- XIAP's activity is modulated by interacting proteins like XAF1 and Smac/DIABLO, and it participates in signal transduction and ubiquitination.
Purpose of the Study:
- To elucidate the multifaceted roles of XIAP in cellular processes.
- To explore the unique translational control mechanisms of XIAP, including Internal Ribosome Entry Site (IRES) mediated synthesis.
- To highlight XIAP as a promising molecular target for therapeutic modulation of apoptosis.
Main Methods:
- Review and synthesis of existing research on XIAP function and regulation.
- Analysis of XIAP's interaction with caspases, regulatory proteins, and its role in signal transduction.
- Investigation of XIAP's unique cap-independent translation mechanism.
Main Results:
- XIAP directly inhibits caspases, controlling apoptosis.
- XIAP is synthesized via an IRES element under cellular stress conditions, independent of cap-dependent translation.
- XIAP influences receptor-mediated signal transduction and protein ubiquitination.
Conclusions:
- XIAP's diverse biological functions and unique translational regulation make it a key target for therapeutic intervention.
- Modulating XIAP offers potential treatments for conditions characterized by inappropriate cell death (e.g., neurodegeneration) or a lack of cell death (e.g., cancer).
- Targeting XIAP provides a novel strategy for controlling apoptosis in various disease contexts.