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1 August 2001 Platelet-Derived Growth Factor Stimulates Phospholipase C-γ1, Extracellular Signal-Regulated Kinase, and Arachidonic Acid Release in Rat Myometrial Cells: Contribution to Cyclic 3′,5′-Adenosine Monophosphate Production and Effect on Cell Proliferation
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Abstract

In the present study, we examined downstream signaling events that followed exposure of cultured rat myometrial cells to platelet-derived growth factor (PDGF) and their effect on cell proliferation. PDGF-BB induced tyrosine phosphorylation of PDGF-β receptors and increased inositol trisphosphate production via the tyrosine phosphorylation of phospholipase (PL)C-γ1. PDGF-BB also increased cAMP synthesis. This increase was potentiated by forskolin and reduced by indomethacin, a cyclooxygenase inhibitor, reflecting a Gs protein-mediated process via prostaglandin biosynthesis. The prostaglandin produced by PDGF was characterized as prostacyclin (PGI2). PDGF-BB increased arachidonic acid (AA) release, which, similarly to cAMP accumulation, was abolished in the presence of AACOCF3, a cytosolic PLA2 inhibitor, and in the absence of Ca2 . U-73122, a potent inhibitor of PLC activity, blocked both the production of inositol phosphates and the AA release triggered by PDGF-BB. Extracellular signal-regulated kinases (ERKs) 1 and 2 are expressed in myometrial cells, and PDGF-BB selectively activated ERK2. PD98059, an inhibitor of the ERK-activating kinase, blocked PDGF-BB-mediated ERK2 activation, AA release, and cAMP production. The results demonstrate that PDGF-BB stimulated cAMP formation through both PLC activation and ERK-dependent AA release and PGI2 biosynthesis. PDGF-BB also increased cell proliferation and [3H]thymidine incorporation. This was abolished by PD98059, demonstrating that the ERK cascade is required for the mitogenic effect of PDGF-BB. Forskolin, which potentiated the cAMP response to PDGF-BB, attenuated both DNA synthesis and ERK activation triggered by PDGF-BB, suggesting the presence of a negative feedback regulation.

Isaline Boulven, Bruno Palmier, Philippe Robin, Monique Vacher, Simone Harbon, and Denis Leiber "Platelet-Derived Growth Factor Stimulates Phospholipase C-γ1, Extracellular Signal-Regulated Kinase, and Arachidonic Acid Release in Rat Myometrial Cells: Contribution to Cyclic 3′,5′-Adenosine Monophosphate Production and Effect on Cell Proliferation," Biology of Reproduction 65(2), 496-506, (1 August 2001). https://doi.org/10.1095/biolreprod65.2.496
Received: 23 October 2000; Accepted: 1 March 2001; Published: 1 August 2001
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