Hsf1 is required for the nuclear translocation of p53 tumor suppressor.
Although the p53 tumor suppressor is most frequently inactivated by genetic mutations, exclusion from the nucleus is also seen in human tumors. We have begun to examine p53 nuclear importation by isolating a series of mutant cells in which the temperature-sensitive murine p53(Val135) mutant is sequestered in the cytoplasm. We previously showed that that three of them (ALTR12, ALTR19, and ALTR25) constituted a single complementation group. Here, we found that ALTR12 cells are more sensitive to heat stress than either ALTR19 or ALTR25 and that there was a complete lack of induction of Hsp70 in response to heat shock. Western blot analysis showed no expression of the Hsf1 transcription factor, and neither heat shock nor azetidine could induce p53 nuclear localization in ALTR12 cells but did in parental A1-5 cells. Suppression of Hsf1 in A1-5 cells with quercetin or an Hsf1 siRNA reduced p53 nuclear importation and inhibited p53-mediated activation of a p21 reporter. Most convincingly, p53 nuclear importation could be restored in ALTR12 cells by introducing an exogenous Hsf1 gene. Collectively, our result suggests that Hsf1 is required for p53 nuclear importation and activation and implies that heat shock factors play a role in the regulation of p53.
Li
Qiang
Q
Department of Cell Biology and Anatomy, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724-5024, USA.
Feldman
Rebecca A
RA
Radhakrishnan
Vijayababu M
VM
Carey
Steven
S
Martinez
Jesse D
JD
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics / Q000502:physiology; D006801:Humans; D008156:Luciferases / Q000235:genetics; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D008156:Luciferases