Impact of PKCdelta on estrogen receptor localization and activity in breast cancer cells.
Regulation of estrogen receptor (ER) function in breast cancer cells is a complex process involving different signalling mechanisms. One signal transduction component that appears to influence ER signalling is protein kinase C (PKC). PKCdelta is a particular isoenzyme of the novel PKC subfamily that plays a role in growth control, differentiation and apoptosis. The aim of the present study was to investigate the impact of PKCdelta on the regulation of the transcriptional activity of the human ERalpha. By using 12-O-tetradecanoylphorbol-13-acetate (TPA), Bryostatin1 and Rottlerin, we show that active PKCdelta is a proproliferative factor in estrogen-dependent breast cancer cells. Furthermore, activation of PKCdelta by TPA resulted in activation and nuclear translocation of ERalpha and in an increase of ER-dependent reporter gene expression. Transfection and expression of the regulatory domain RDdelta of PKCdelta, which is inhibitory to PKCdelta, inhibited the TPA-induced ERalpha activation and translocation. ERalpha was not phosphorylated by PKCdelta; however, glycogen synthase kinase-3 (GSK3) was identified as a substrate of PKCdelta. The expression of RDdelta resulted in a decrease of TPA-induced GSK3 phosphorylation and translocation into the nucleus. We suggest that GSK3 plays a role in the PKCdelta-related nuclear translocation of ERalpha.
De Servi
Barbara
B
Deutsches Krebsforschungszentrum, Hormones and Signal Transduction, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
Hermani
Alexander
A
Medunjanin
Senad
S
Mayer
Doris
D
D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000502:physiology; D005260:Female; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051745:Protein Kinase C-delta; D011960:Receptors, Estrogen / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014162:Transfection
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen; D004958:Estradiol; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D038362:Glycogen Synthase Kinase 3; D013755:Tetradecanoylphorbol Acetate