PKA-Mediated Stabilization of FoxH1 Negatively Regulates ERα Activity

• DOI: 10.1007/s10059-009-0099-7
• Publication Date: 2009-08-26T13:52:47Z
• Authors: Jinah Yum Yum; Hyung Min Jeong; Seulki Kim; Jin Won Seo; Younho Han; Kwang-Youl Lee; Chang-Yeol Yeo
• Keywords: Protein Synthesis Inhibitors; 0301 basic medicine; 0303 health sciences; Estradiol; Protein Stability; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Colforsin; Estrogen Receptor alpha; Forkhead Transcription Factors; Isoquinolines; Response Elements; Cyclic AMP-Dependent Protein Kinases; Cell Line; Enzyme Activation; 03 medical and health sciences; Gene Expression Regulation; Cell Line, Tumor; Humans; RNA Interference; Cycloheximide; Luciferases; Protein Kinase Inhibitors

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.