p53 suppresses the c-Myb-induced activation of heat shock transcription factor 3.
Expression of heat shock proteins (HSPs) is controlled by heat shock transcription factors (HSFs). Vertebrates express multiple HSFs whose activities may be regulated by distinct signals. HSF3 is specifically activated in unstressed proliferating cells by direct binding to the c-myb proto-oncogene product (c-Myb), which plays an important role in cellular proliferation. This suggests that the c-Myb-induced HSF3 activation may contribute to the growth-regulated expression of HSPs. Here we report that the p53 tumor suppressor protein directly binds to HSF3 and blocks the interaction between c-Myb and HSF3. In addition, p53 stimulates the degradation of c-Myb through a proteasome-dependent mechanism, which is, at least partly, mediated by induction of Siah in certain types of cells. Induction of p53 by a genotoxic reagent in DT40 cells disrupts the HSF3-c-Myb interaction and down-regulates the expression of certain HSPs. Mutated forms of p53 found in certain tumors did not inhibit c-Myb-induced HSF3 activation. The regulation of HSF3 activity by c-Myb and p53 sheds light on the molecular events that govern HSP expression during cellular proliferation and apoptosis.
Tanikawa
J
J
Laboratory of Molecular Genetics, RIKEN Tsukuba Life Sciences Center, Japan Science and Technology, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
Ichikawa-Iwata
E
E
Kanei-Ishii
C
C
Nakai
A
A
Matsuzawa
S
S
Reed
J C
JC
Ishii
S
S
D000818:Animals; D030161:Avian Proteins; D002460:Cell Line; D002645:Chickens; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D030161:Avian Proteins; D004268:DNA-Binding Proteins; C095720:HSF3 protein, Gallus gallus; D006360:Heat-Shock Proteins; C000715470:MAS1 protein, human; D009097:Multienzyme Complexes; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb; D011994:Recombinant Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex