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Molecular chaperones and the stress of oncogenesis

Abstract

Protein-damaging stresses induce the expression of ‘heat-shock proteins’, which have essential roles in protecting cells from the potentially lethal effects of stress and proteotoxicity. These stress-protective heat-shock proteins are often overexpressed in cells of various cancers and have been suggested to be contributing factors in tumorigenesis. An underlying basis of oncogenesis is the acquisition and accumulation of mutations that provide the transformed cell with the combined characteristics of deregulated cell proliferation and suppressed cell death. Heat-shock proteins with dual roles as regulators of protein conformation and stress sensors may therefore have intriguing and central roles in both cell proliferation and apoptosis. It has been established that heat-shock proteins exhibit specificity to particular classes of polypeptide substrates and client proteins in vivo, and that chaperones can stabilize mutations that affect the folded conformation. Likewise, overexpression of chaperones has also been shown to protect cells against apoptotic cell death. The involvement of chaperones, therefore, in such diverse roles might suggest novel anticancer therapeutic approaches targeting heat-shock protein function for a broad spectrum of tumor types.

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Acknowledgements

We thank Sue Fox for her expert assistance with the preparation of the figures. Work carried out in the authors’ labs is supported by the National Institutes of Health (NIGMS 38109) (RM), the Huntington Disease Society of America Coalition for the Cure (RM), the ALS association (RM) and the Natural Science and Engineering Research Council (DM).

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Mosser, D., Morimoto, R. Molecular chaperones and the stress of oncogenesis. Oncogene 23, 2907–2918 (2004). https://doi.org/10.1038/sj.onc.1207529

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