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Mechanisms controlling cellular suicide: role of Bcl-2 and caspases
R T Allen1, M W Cluck, D K Agrawal
1Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
Abstract:
Apoptosis is an essential and highly conserved mode of cell death that is important for normal development, host defense and suppression of oncogenesis. Faulty regulation of apoptosis has been implicated in degenerative conditions, vascular diseases, AIDS and cancer. Among the numerous proteins and genes involved, members of the Bcl-2 family play a central role to inhibit or promote apoptosis. In this article, we present up-to-date information and recent discoveries regarding biochemical functions of Bcl-2 family proteins, positive and negative interactions between these proteins, and their modification and regulation by either proteolytic cleavage or by cytosolic kinases, such as Raf-1 and stress-activated protein kinases. We have critically reviewed the functional role of caspases and the consequences of cleaving key substrates, including lamins, poly(ADP ribose) polymerase and the Rb protein. In addition, we have presented the latest Fas-induced signalling mechanism as a model for receptor-linked caspase regulation. Finally, the structural and functional interactions of Ced-4 and its partial mammalian homologue, apoptosis protease activating factor-1 (Apaf-1), are presented in a model which includes other Apafs. This model culminates in a caspase/Apaf regulatory cascade to activate the executioners of programmed cell death following cytochrome c release from the mitochondria of mammalian cells. The importance of these pathways in the treatment of disease is highly dependent on further characterization of genes and other regulatory molecules in mammals.
Insights
Programmed cell death, or apoptosis, is vital for development and preventing cancer. This review details Bcl-2 family proteins, caspases, and signaling pathways crucial for apoptosis regulation and disease treatment.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Apoptosis is a fundamental cellular process critical for development, immunity, and cancer prevention.
- Dysregulation of apoptosis is linked to various diseases, including cancer, AIDS, and degenerative conditions.
- The Bcl-2 protein family is central to regulating apoptosis, either promoting or inhibiting the process.
Purpose of the Study:
- To provide an updated overview of Bcl-2 family protein functions and interactions.
- To review the role of caspases and their substrates in apoptosis.
- To present current models of Fas-induced signaling and the Ced-4/Apaf-1 pathway in mammalian apoptosis.
Main Methods:
- Literature review and critical analysis of existing research on apoptosis.
- Detailed examination of biochemical functions and regulatory mechanisms of Bcl-2 family proteins.
- Exploration of caspase activation pathways, including substrate cleavage and signaling cascades.
Main Results:
- Bcl-2 family proteins interact to control apoptosis.
- Caspases execute apoptosis by cleaving key cellular substrates like lamins and Rb protein.
- Fas-induced signaling and the mitochondrial pathway involving cytochrome c, Apaf-1, and caspases are key regulatory mechanisms.
Conclusions:
- Understanding Bcl-2 family proteins, caspases, and their regulatory pathways is essential for developing disease treatments.
- Further characterization of mammalian genes and regulatory molecules involved in apoptosis is crucial.
- Targeting apoptosis pathways holds significant therapeutic potential for various diseases.