PKA-mediated stabilization of FoxH1 negatively regulates ERalpha activity.
Estrogen receptor alpha (ERalpha) mediates the mitogenic effects of estrogen. ERalpha signaling regulates the normal growth and differentiation of mammary tissue, but uncontrolled ERalpha activation increases the risk to breast cancer. Estrogen binding induces ligand-dependent ERalpha activation, thereby facilitating ERalpha dimerization, promoter binding and coactivator recruitment. ERalpha can also be activated in a ligand-independent manner by many signaling pathways, including protein kinase A (PKA) signaling. However, in several ERalpha-positive breast cancer cells, PKA inhibits estrogen-dependent cell growth. FoxH1 represses the transcriptional activities of estrogen receptors and androgen receptors (AR). Interestingly, FoxH1 has been found to inhibit the PKA-induced and ligand-induced activation of AR. In the present study, we examined the effects of PKA activation on the ability of FoxH1 to represses ERalpha transcriptional activity. We found that PKA increases the protein stability of FoxH1, and that FoxH1 inhibits PKA-induced and estradiol-induced activation of an estrogen response element (ERE). Furthermore, in MCF7 cells, FoxH1 knockdown increased the PKA-induced and estradiol-induced activation of the ERE. These results suggest that PKA can negatively regulate ERalpha, at least in part, through FoxH1.
Yum
Jinah
J
Department of Life Science and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
Jeong
Hyung Min
HM
Kim
Seulki
S
Seo
Jin Won
JW
Han
Younho
Y
Lee
Kwang-Youl
KY
Yeo
Chang-Yeol
CY
D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology
D047628:Estrogen Receptor alpha; C510350:FOXH1 protein, human; D051858:Forkhead Transcription Factors; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D013449:Sulfonamides; D005576:Colforsin; D004958:Estradiol; D003513:Cycloheximide; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide