TRANSCRIPTIONAL ACTIVITY OF HEAT-SHOCK FACTOR-1 AT 37 DEGREES-C IS REPRESSED THROUGH PHOSPHORYLATION ON 2 DISTINCT SERINE RESIDUES BY GLYCOGEN-SYNTHASE KINASE 3-ALPHA AND PROTEIN-KINASES C-ALPHA, AND C-ZETA

Heat shock factor 1 (HSF1) is the key transcriptional regulator of the heat shock genes that protect cells from environmental stress. Howeve r, because heat shock gene expression is deleterious to growth and dev elopment, we have examined mechanisms for HSF1 repression at growth te mperatures, focusing on the role of phosphorylation. Mitogen-activated protein kinases (MAPKs) of the ERR family phosphorylate HSF1 and repr esses transcriptional function. The mechanism of repression involves i nitial phosphorylation by MAP kinase on serine 307, which primes HSF1 for secondary phosphorylation by glycogen synthase kinase 3 on a key r esidue in repression (serine 303). In vivo expression of glycogen synt hase kinase 3 (alpha or beta) thus represses HSF1 through phosphorylat ion of serine 303. HSF1 is also phosphorylated by MAPK in vitro on a s econd residue (serine 363) adjacent to activation domain 1, and this r esidue is additionally phosphorylated by protein kinase C. In vivo, HS F1 is repressed through phosphorylation of this residue by protein kin ase C alpha or -zeta but not MAPK. Regulation at 37 degrees C, therefo re, 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.