PKA-Mediated Stabilization of FoxH1 Negatively Regulates ERα Activity
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
DOI:
10.1007/s10059-009-0099-7
Publication Date:
2009-08-26T13:52:47Z
AUTHORS (7)
ABSTRACT
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.
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CITATIONS (9)
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