Induction of Gαs contributes to the paradoxical stimulation of cytosolic phospholipase A2α expression by cortisol in human amnion fibroblasts

Chunming Guo, Jianneng Li, Leslie Myatt, Xiaoou Zhu, Kang Sun

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Cytosolic phospholipase A (cPLA) catalyzes the formation of arachidonic acid in prostaglandin synthesis. In contrast to the well-described down-regulation of cPLA, up-regulation of cPLA by glucocorticoids has been reported in human amnion fibroblasts, which may play a key role in parturition. The mechanisms underlying this paradoxical induction of cPLA by glucocorticoids remain largely unknown. Using cultured human amnion fibroblasts, we found that the induction of cPLA by cortisol required ongoing transcription and synthesis of at least one other protein. The induction of cPLA by cortisol was abolished by mutagenesis of a glucocorticoid response element (GRE) in the promoter. The same GRE was found mediating the classical inhibition of cPLA expression by cortisol in human fetal lung fibroblasts (HFL-1). Cortisol increased Gαs expression in amnion fibroblasts but not in HFL-1 cells. Inhibition of Gαs with NF449 attenuated the phosphorylation of cAMP response element-binding protein-1 (CREB-1) and the induction of cPLA by cortisol in amnion fibroblasts. Both glucocorticoid receptor (GR) and CREB-1 were found bound to the GRE upon cortisol stimulation of amnion fibroblasts. The induction of cPLA by cortisol was blocked by GR antagonist RU486 or protein kinase A inhibitor H89 or dominantnegative CREB-1. In conclusion, cortisol activates the cAMP/protein kinase A/CREB-1 pathway via Gαs induction, and the phosphorylated CREB-1 interacts with GR at the GRE to promote cPLA expression in amnion fibroblasts.

Original languageEnglish (US)
Pages (from-to)1052-1061
Number of pages10
JournalMolecular Endocrinology
Volume24
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Fingerprint

Cytosolic Phospholipases A2
Amnion
Hydrocortisone
Cyclic AMP Response Element-Binding Protein
Fibroblasts
Glucocorticoids
Response Elements
Glucocorticoid Receptors
Cyclic AMP-Dependent Protein Kinases
Phospholipases A
Protein Kinase Inhibitors
Arachidonic Acid
Mutagenesis
Prostaglandins
Up-Regulation
Down-Regulation
Phosphorylation
Parturition
Lung

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology
  • Medicine(all)

Cite this

Induction of Gαs contributes to the paradoxical stimulation of cytosolic phospholipase A2α expression by cortisol in human amnion fibroblasts. / Guo, Chunming; Li, Jianneng; Myatt, Leslie; Zhu, Xiaoou; Sun, Kang.

In: Molecular Endocrinology, Vol. 24, No. 5, 05.2010, p. 1052-1061.

Research output: Contribution to journalArticle

@article{2d04760b41b94776b4cb4f5877a45004,
title = "Induction of Gαs contributes to the paradoxical stimulation of cytosolic phospholipase A2α expression by cortisol in human amnion fibroblasts",
abstract = "Cytosolic phospholipase A (cPLA2α) catalyzes the formation of arachidonic acid in prostaglandin synthesis. In contrast to the well-described down-regulation of cPLA2α, up-regulation of cPLA2α by glucocorticoids has been reported in human amnion fibroblasts, which may play a key role in parturition. The mechanisms underlying this paradoxical induction of cPLA2α by glucocorticoids remain largely unknown. Using cultured human amnion fibroblasts, we found that the induction of cPLA2α by cortisol required ongoing transcription and synthesis of at least one other protein. The induction of cPLA 2α by cortisol was abolished by mutagenesis of a glucocorticoid response element (GRE) in the promoter. The same GRE was found mediating the classical inhibition of cPLA2α expression by cortisol in human fetal lung fibroblasts (HFL-1). Cortisol increased Gαs expression in amnion fibroblasts but not in HFL-1 cells. Inhibition of Gαs with NF449 attenuated the phosphorylation of cAMP response element-binding protein-1 (CREB-1) and the induction of cPLA2α by cortisol in amnion fibroblasts. Both glucocorticoid receptor (GR) and CREB-1 were found bound to the GRE upon cortisol stimulation of amnion fibroblasts. The induction of cPLA2α by cortisol was blocked by GR antagonist RU486 or protein kinase A inhibitor H89 or dominantnegative CREB-1. In conclusion, cortisol activates the cAMP/protein kinase A/CREB-1 pathway via Gαs induction, and the phosphorylated CREB-1 interacts with GR at the GRE to promote cPLA2α expression in amnion fibroblasts.",
author = "Chunming Guo and Jianneng Li and Leslie Myatt and Xiaoou Zhu and Kang Sun",
year = "2010",
month = "5",
doi = "10.1210/me.2009-0488",
language = "English (US)",
volume = "24",
pages = "1052--1061",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "5",

}

TY - JOUR

T1 - Induction of Gαs contributes to the paradoxical stimulation of cytosolic phospholipase A2α expression by cortisol in human amnion fibroblasts

AU - Guo, Chunming

AU - Li, Jianneng

AU - Myatt, Leslie

AU - Zhu, Xiaoou

AU - Sun, Kang

PY - 2010/5

Y1 - 2010/5

N2 - Cytosolic phospholipase A (cPLA2α) catalyzes the formation of arachidonic acid in prostaglandin synthesis. In contrast to the well-described down-regulation of cPLA2α, up-regulation of cPLA2α by glucocorticoids has been reported in human amnion fibroblasts, which may play a key role in parturition. The mechanisms underlying this paradoxical induction of cPLA2α by glucocorticoids remain largely unknown. Using cultured human amnion fibroblasts, we found that the induction of cPLA2α by cortisol required ongoing transcription and synthesis of at least one other protein. The induction of cPLA 2α by cortisol was abolished by mutagenesis of a glucocorticoid response element (GRE) in the promoter. The same GRE was found mediating the classical inhibition of cPLA2α expression by cortisol in human fetal lung fibroblasts (HFL-1). Cortisol increased Gαs expression in amnion fibroblasts but not in HFL-1 cells. Inhibition of Gαs with NF449 attenuated the phosphorylation of cAMP response element-binding protein-1 (CREB-1) and the induction of cPLA2α by cortisol in amnion fibroblasts. Both glucocorticoid receptor (GR) and CREB-1 were found bound to the GRE upon cortisol stimulation of amnion fibroblasts. The induction of cPLA2α by cortisol was blocked by GR antagonist RU486 or protein kinase A inhibitor H89 or dominantnegative CREB-1. In conclusion, cortisol activates the cAMP/protein kinase A/CREB-1 pathway via Gαs induction, and the phosphorylated CREB-1 interacts with GR at the GRE to promote cPLA2α expression in amnion fibroblasts.

AB - Cytosolic phospholipase A (cPLA2α) catalyzes the formation of arachidonic acid in prostaglandin synthesis. In contrast to the well-described down-regulation of cPLA2α, up-regulation of cPLA2α by glucocorticoids has been reported in human amnion fibroblasts, which may play a key role in parturition. The mechanisms underlying this paradoxical induction of cPLA2α by glucocorticoids remain largely unknown. Using cultured human amnion fibroblasts, we found that the induction of cPLA2α by cortisol required ongoing transcription and synthesis of at least one other protein. The induction of cPLA 2α by cortisol was abolished by mutagenesis of a glucocorticoid response element (GRE) in the promoter. The same GRE was found mediating the classical inhibition of cPLA2α expression by cortisol in human fetal lung fibroblasts (HFL-1). Cortisol increased Gαs expression in amnion fibroblasts but not in HFL-1 cells. Inhibition of Gαs with NF449 attenuated the phosphorylation of cAMP response element-binding protein-1 (CREB-1) and the induction of cPLA2α by cortisol in amnion fibroblasts. Both glucocorticoid receptor (GR) and CREB-1 were found bound to the GRE upon cortisol stimulation of amnion fibroblasts. The induction of cPLA2α by cortisol was blocked by GR antagonist RU486 or protein kinase A inhibitor H89 or dominantnegative CREB-1. In conclusion, cortisol activates the cAMP/protein kinase A/CREB-1 pathway via Gαs induction, and the phosphorylated CREB-1 interacts with GR at the GRE to promote cPLA2α expression in amnion fibroblasts.

UR - http://www.scopus.com/inward/record.url?scp=77954848124&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954848124&partnerID=8YFLogxK

U2 - 10.1210/me.2009-0488

DO - 10.1210/me.2009-0488

M3 - Article

C2 - 20203101

AN - SCOPUS:77954848124

VL - 24

SP - 1052

EP - 1061

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 5

ER -