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Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability

Oncogene volume 29, pages 4216–4224 (2010)Cite this article

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Abstract

A single heat shock factor (HSF), mediating the heat shock response, exists from yeast to Drosophila, whereas several related HSFs have been found in mammals. This raises the question of the specific or redundant functions of the different members of the HSF family and in particular of HSF1 and HSF2, which are both ubiquitously expressed. Using immortalized mouse embryonic fibroblasts (iMEFs) derived from wild-type, Hsf1−/−, Hsf2−/− or double-mutant mice, we observed the distinctive behaviors of these mutants with respect to proteasome inhibition. This proteotoxic stress reduces to the same extent the viability of Hsf1−/−- and Hsf2−/−-deficient cells, but through different underlying mechanisms. Contrary to Hsf2−/− cells, Hsf1−/− cells are unable to induce pro-survival heat shock protein expression. Conversely, proteasome activity is lower in Hsf2−/− cells and the expression of some proteasome subunits, such as Psmb5 and gankyrin, is decreased. As gankyrin is an oncoprotein involved in p53 degradation, we analyzed the status of p53 in HSF-deficient iMEFs and observed that it was strongly stabilized in Hsf2−/− cells. This study points a new role for HSF2 in the regulation of protein degradation and suggests that pan-HSF inhibitors could be valuable tools to reduce chemoresistance to proteasome inhibition observed in cancer therapy.

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Acknowledgements

This work was supported by Cancéropole Grand Ouest and CNRS. SL and FLM were supported by a fellowship from the French Ministry of Higher Education and Research (MENRT), and FD by a fellowship from the ‘Association pour la Recherche sur le Cancer’ (ARC). We thank Dr V Mezger (UMR CNRS 7216, Paris, France) for the gift of immortalized MEFs, and V Noel for the help in in silico analysis. We also thank Frédéric Percevault for the establishment of a stable clone expressing HSF2 from Hsf2−/− iMEFs.

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  1. Homéostasie Intracellulaire des Protéines, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140–Génomique Fonctionnelle Agronomie et Santé-, Université de Rennes1, Rennes, France

    S Lecomte, F Desmots, P Le Goff, D Michel & Y Le Dréan

  2. Centre de Biologie du Développement, UMR CNRS 5547, Université Toulouse 3, Toulouse, France

    F Le Masson & E S Christians

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  1. S Lecomte
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Correspondence to Y Le Dréan.

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Lecomte, S., Desmots, F., Le Masson, F. et al. Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability. Oncogene 29, 4216–4224 (2010). https://doi.org/10.1038/onc.2010.171

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