Modulators of cellular protein phosphorylation alter the trans-activation function of human progesterone receptor and the biological activity of progesterone antagonists.
Addition of progesterone to breast cancer cells in vivo increases phosphorylation of human progesterone receptor (PR), suggesting that phosphorylation has a regulatory role in producing the activated form of receptor. Kinetic analysis indicates that hormone-dependent phosphorylation is sequential and that early stages of phosphorylation(s) are closely associated with enhancement of PR-DNA binding while later stages are associated with a trans-activation function. Various agents that stimulate cellular protein phosphorylation (8-Br cAMP, okadaic acid, TPA) functionally synergize with progesterone to enhance progesterone-dependent PR trans-activation in intact cells. These results suggest that protein phosphorylation does have a role in modulating the trans-activation function of PR in vivo. They also demonstrate cross-talk between second messenger signal transduction pathways and nuclear steroid receptors. Whether the phosphorylated target that provides the link between these two signal transduction pathways is PR itself or another protein involved in PR-mediated gene transcription is not known. Positive cooperative interactions were also observed between cAMP signaling pathways and the progesterone antagonist RU486, that resulted in RU486 exerting substantial agonist activities. This ability of cross-talk between second messenger and steroid receptor signal transduction pathways to override the antagonistic effects of RU486 suggests a novel mechanism to explain the problem of resistance to clinically important steroid antagonists.
Edwards
D P
DP
Department of Pathology, University of Colorado Health Sciences Center, Denver 80262.
Weigel
N L
NL
Nordeen
S K
SK
Beck
C A
CA
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D001943:Breast Neoplasms; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D004988:Ethers, Cyclic / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D015735:Mifepristone / Q000494:pharmacology*; D019319:Okadaic Acid; D010710:Phosphates / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D011980:Receptors, Progesterone / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004988:Ethers, Cyclic; D010710:Phosphates; D011980:Receptors, Progesterone; D019319:Okadaic Acid; D015124:8-Bromo Cyclic Adenosine Monophosphate; D015735:Mifepristone; D000105:Acetyl Coenzyme A; D010749:Phosphoprotein Phosphatases; D013755:Tetradecanoylphorbol Acetate