Transcriptional activity of heat shock factor 1 at 37 degrees C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases Calpha and Czeta.
Heat shock factor 1 (HSF1) is the key transcriptional regulator of the heat shock genes that protect cells from environmental stress. However, because heat shock gene expression is deleterious to growth and development, we have examined mechanisms for HSF1 repression at growth temperatures, focusing on the role of phosphorylation. Mitogen-activated protein kinases (MAPKs) of the ERK family phosphorylate HSF1 and represses transcriptional function. The mechanism of repression involves initial phosphorylation by MAP kinase on serine 307, which primes HSF1 for secondary phosphorylation by glycogen synthase kinase 3 on a key residue in repression (serine 303). In vivo expression of glycogen synthase kinase 3 alpha or beta thus represses HSF1 through phosphorylation of serine 303. HSF1 is also phosphorylated by MAPK in vitro on a second residue (serine 363) adjacent to activation domain 1, and this residue is additionally phosphorylated by protein kinase C. In vivo, HSF1 is repressed through phosphorylation of this residue by protein kinase Calpha or -zeta but not MAPK. Regulation at 37 degrees C, therefore, involves the action of three protein kinase cascades that repress HSF1 through phosphorylation of serine residues 303, 307, and 363 and may promote growth by suppressing the heat shock response.
Chu
B
B
Department of Adult Oncology, Dana Farber Cancer Institute and Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zhong
R
R
Soncin
F
F
Stevenson
M A
MA
Calderwood
S K
SK
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D012694:Serine / Q000378:metabolism*; D013696:Temperature; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000099221:Protein Kinase C zeta
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D007527:Isoenzymes; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D012694:Serine; D014157:Transcription Factors; D000099221:Protein Kinase C zeta; C496630:Prkca protein, mouse