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Convergence of 3',5'-Cyclic Adenosine 5'-Monophosphate/Protein Kinase A and Glycogen Synthase Kinase-3β/β-Catenin Signaling in Corpus Luteum Progesterone Synthesis

Departments of Pharmacology and Experimental Neuroscience (L.R., J.S.D.), Obstetrics and Gynecology (C.A.M., X.H., J.S.D.), Biochemistry and Molecular Biology (D.M., J.S.D.), and Environmental, Agricultural, and Occupational Health (T.A.W.) and Olson Center for Women’s Health (C.J., J.S.D.), University of Nebraska Medical Center, Omaha, NE 68198; Department of Cell Biology and Physiology (A.J.Z.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; and Department of Veterans Affairs Medical Center (T.A.W., X.H., J.S.D.), Omaha, Nebraska 68105

Address all correspondence and requests for reprints to: Dr. John S. Davis, Department of Obstetrics and Gynecology, Olson Center for Women’s Health, 3255 Nebraska Medical Center, Omaha, Nebraska 68198. E-mail: jsdavis{at}unmc.edu.

Progesterone secretion by the steroidogenic cells of the corpus luteum (CL) is essential for reproduction. Progesterone synthesis is under the control of LH, but the exact mechanism of this regulation is unknown. It is established that LH stimulates the LH receptor/choriogonadotropin receptor, a G-protein coupled receptor, to increase cAMP and activate cAMP-dependent protein kinase A (PKA). In the present study, we tested the hypothesis that cAMP/PKA-dependent regulation of the Wnt pathway components glycogen synthase kinase (GSK)-3β and β-catenin contributes to LH-dependent steroidogenesis in luteal cells. We observed that LH via a cAMP/PKA-dependent mechanism stimulated the phosphorylation of GSK3β at N-terminal Ser9 causing its inactivation and resulted in the accumulation of β-catenin. Overexpression of N-terminal truncated β-catenin (90 β-catenin), which lacks the phosphorylation sites responsible for its destruction, significantly augmented LH-stimulated progesterone secretion. In contrast, overexpression of a constitutively active mutant of GSK3β (GSK-S9A) reduced β-catenin levels and inhibited LH-stimulated steroidogenesis. Chromatin immunoprecipitation assays demonstrated the association of β-catenin with the proximal promoter of the StAR gene, a gene that expresses the steroidogenic acute regulatory protein, which is a cholesterol transport protein that controls a rate-limiting step in steroidogenesis. Collectively these data suggest that cAMP/PKA regulation of GSK3β/β-catenin signaling may contribute to the acute increase in progesterone production in response to LH.