Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability.
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.
Lecomte
S
S
Homéostasie Intracellulaire des Protéines, UMR CNRS 6026, Interactions Cellulaires et Moléculaires, IFR 140-Génomique Fonctionnelle Agronomie et Santé-, Université de Rennes1, Rennes, France.
Desmots
F
F
Le Masson
F
F
Le Goff
P
P
Michel
D
D
Christians
E S
ES
Le Dréan
Y
Y
D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy; D061988:Proteasome Inhibitors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C490017:Hsf1 protein, mouse; C531390:Hsf2 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin