Heat shock proteins--modulators of apoptosis in tumour cells.
Apoptosis is a genetically programmed, physiological method of cell destruction. A variety of genes are now recognised as positive or negative regulators of this process. Expression of inducible heat shock proteins (hsp) is known to correlate with increased resistance to apoptosis induced by a range of diverse cytotoxic agents and has been implicated in chemotherapeutic resistance of tumours and carcinogenesis. Intensive research on apoptosis over the past number of years has provided significant insights into the mechanisms and molecular events that occur during this process. The modulatory effects of hsps on apoptosis are well documented, however, the mechanisms of hsp-mediated protection against apoptosis remain to be fully defined, although several hypotheses have been proposed. Elucidation of these mechanisms should reveal novel targets for manipulating the sensitivity of leukaemic cells to therapy. This review aims to explain the currently understood process of apoptosis and the effects of hsps on this process. Several proposed mechanisms for hsp protection against apoptosis and the therapeutic implications of hsps in leukaemia are also discussed.
Creagh
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Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Ireland.
Sheehan
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Cotter
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D005057:Eukaryotic Cells / Q000166:cytology; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects; D018384:Oxidative Stress; D017510:Protein Folding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014158:Transcription, Genetic; D019014:fas Receptor / Q000502:physiology
D000970:Antineoplastic Agents; D003574:Cytochrome c Group; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D019014:fas Receptor; D020169:Caspases