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.
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U2 - 10.1210/me.2009-0488
DO - 10.1210/me.2009-0488
M3 - Article
C2 - 20203101
AN - SCOPUS:77954848124
SN - 0888-8809
VL - 24
SP - 1052
EP - 1061
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 5
ER -