Convergence of 3′,5′-cyclic adenosine 5′-monophosphate/ protein kinase A and glycogen synthase kinase-3β/β-catenin signaling in corpus luteum progesterone synthesis

Lynn Roy, Claudia A. McDonald, Chao Jiang, Dulce Maroni, Anthony J. Zeleznik, Todd A Wyatt, Xiaoying Hou, John S Davis

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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 (Δ90 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.

Original languageEnglish (US)
Pages (from-to)5036-5045
Number of pages10
JournalEndocrinology
Volume150
Issue number11
DOIs
StatePublished - Nov 1 2009

Fingerprint

Glycogen Synthase Kinase 3
Catenins
Corpus Luteum
Cyclic AMP-Dependent Protein Kinases
Cyclic AMP
Progesterone
Phosphorylation
Luteal Cells
LH Receptors
Glycogen Synthase Kinases
Wnt Signaling Pathway
Chromatin Immunoprecipitation
Chorionic Gonadotropin
G-Protein-Coupled Receptors
Genes
Reproduction
Carrier Proteins
Cholesterol

ASJC Scopus subject areas

  • Endocrinology

Cite this

Convergence of 3′,5′-cyclic adenosine 5′-monophosphate/ protein kinase A and glycogen synthase kinase-3β/β-catenin signaling in corpus luteum progesterone synthesis. / Roy, Lynn; McDonald, Claudia A.; Jiang, Chao; Maroni, Dulce; Zeleznik, Anthony J.; Wyatt, Todd A; Hou, Xiaoying; Davis, John S.

In: Endocrinology, Vol. 150, No. 11, 01.11.2009, p. 5036-5045.

Research output: Contribution to journalArticle

Roy, Lynn ; McDonald, Claudia A. ; Jiang, Chao ; Maroni, Dulce ; Zeleznik, Anthony J. ; Wyatt, Todd A ; Hou, Xiaoying ; Davis, John S. / Convergence of 3′,5′-cyclic adenosine 5′-monophosphate/ protein kinase A and glycogen synthase kinase-3β/β-catenin signaling in corpus luteum progesterone synthesis. In: Endocrinology. 2009 ; Vol. 150, No. 11. pp. 5036-5045.
@article{8665ae926b144aed8d185b80d100dc1a,
title = "Convergence of 3′,5′-cyclic adenosine 5′-monophosphate/ protein kinase A and glycogen synthase kinase-3β/β-catenin signaling in corpus luteum progesterone synthesis",
abstract = "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 (Δ90 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.",
author = "Lynn Roy and McDonald, {Claudia A.} and Chao Jiang and Dulce Maroni and Zeleznik, {Anthony J.} and Wyatt, {Todd A} and Xiaoying Hou and Davis, {John S}",
year = "2009",
month = "11",
day = "1",
doi = "10.1210/en.2009-0771",
language = "English (US)",
volume = "150",
pages = "5036--5045",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "11",

}

TY - JOUR

T1 - Convergence of 3′,5′-cyclic adenosine 5′-monophosphate/ protein kinase A and glycogen synthase kinase-3β/β-catenin signaling in corpus luteum progesterone synthesis

AU - Roy, Lynn

AU - McDonald, Claudia A.

AU - Jiang, Chao

AU - Maroni, Dulce

AU - Zeleznik, Anthony J.

AU - Wyatt, Todd A

AU - Hou, Xiaoying

AU - Davis, John S

PY - 2009/11/1

Y1 - 2009/11/1

N2 - 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 (Δ90 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.

AB - 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 (Δ90 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.

UR - http://www.scopus.com/inward/record.url?scp=70350321017&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350321017&partnerID=8YFLogxK

U2 - 10.1210/en.2009-0771

DO - 10.1210/en.2009-0771

M3 - Article

C2 - 19819952

AN - SCOPUS:70350321017

VL - 150

SP - 5036

EP - 5045

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 11

ER -