MODULATION OF MOUSE ESTROGEN-RECEPTOR TRANSCRIPTION ACTIVITY BY PROTEIN-KINASE-C-DELTA

The effect of protein kinase C (PKC) delta on the transcriptional acti vity of the mouse estrogen receptor was investigated. The receptor was expressed transiently in Cos-1 and NIH3T3 cells in the presence of wi ld-type, dominant negative or constitutively active forms of PKC delta . Transfection experiments demonstrated that PKC delta stimulated both unliganded and liganded estrogen receptor transcriptional activity. T his stimulatory effect was not observed using PKC alpha or PKC epsilon . 4-Hydorxytamoxifen and the pure anti-estrogen ICI 164,384 reduced re ceptor transcriptional activity in the presence of PKC delta. The stim ulatory effect of PKC delta on estrogen receptor transcriptional activ ity was mediated by the N-terminal activation function 1 (AF-1) domain . The reduced stimulatory effect of PKC delta on transcriptional activ ity of the phosphorylation defective mutant of estrogen receptor sugge sts that phosphorylation of serine 122 in the AF-1 region may mediate the modulatory effect of PKC delta. Wild-type PKC delta caused a twofo ld increase in estrogen receptor phosphorylation, while a dominant neg ative mutant of PKC delta reduced the receptor phosphorylation to five percent of that caused by wild-type PKC delta. Our results suggest th at PKC delta participates in the signaling pathways that lead to estro gen receptor phosphorylation and its effect on estrogen receptor trans criptional activation is both cell type and promoter specific.