MITOGEN-ACTIVATED AND CYCLIN-DEPENDENT PROTEIN-KINASES SELECTIVELY AND DIFFERENTIALLY MODULATE TRANSCRIPTIONAL ENHANCEMENT BY THE GLUCOCORTICOID RECEPTOR

Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MA PK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor r esidues observed in vivo; MAPK phosphorylates receptor residues threon ine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232, Mutations in these kinases have opposite effects on recep tor transcriptional activity in vivo. Receptor-dependent transcription al enhancement is reduced in yeast strains deficient in the catalytic (p34(CDC28)) or certain regulatory (cyclin) subunits of CDK complexes and is increased in a strain devoid of the mammalian MAPK homologs FUS 3 and KSS1. These findings indicate that the glucocorticoid receptor i s a target for multiple kinases in vivo, which either positively or ne gatively regulate receptor transcriptional enhancement. The control of receptor transcriptional activity via phosphorylation provides an inc reased array of regulatory inputs that, in addition to steroid hormone s, can influence receptor function.