Platelet-derived Growth Factor-specific Regulation of theJE Promoter in Rat Aortic Smooth Muscle Cells

Vladimir Y Bogdanov,Mark B Taubman,Michael Poon

doi:10.1074/jbc.273.38.24932

Vladimir Y Bogdanov, Mark B Taubman + Show 1 more

Open Access

https://doi.org/10.1074/jbc.273.38.24932

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Abstract

JE is a member of the family of "immediate early" genes induced by growth factors and cytokines. JE encodes a low molecular weight secretory glycoprotein analogous to the human monocyte chemoattractant protein, MCP-1. JE and MCP-1 proteins are thought to play an important role in inflammation and in the recruitment of monocyte/macrophages to the vessel wall during the development of atherosclerosis. We have previously reported that the induction of JE in rat aortic smooth muscle cells (SMC) was specific to platelet-derived growth factor (PDGF) and was not seen with other growth agonists. Using a luciferase reporter system and transient transfection assays of rat aortic SMC, we now report the identification of a region in the proximal rat JE promoter that is responsive to PDGF but not to other growth factors (angiotensin II and alpha-thrombin) or cytokines (interleukin 1-beta and tumor necrosis factor-alpha). The full response to PDGF (approximately 6-fold) requires the cooperative activity of two potentially novel cis-acting elements, at positions -146 to -128 and -84 to -59. While each element produces a different pattern in electrophoretic mobility shift assays, they appear to bind the same PDGF-responsive species. Further analysis of these regions should provide important insights into PDGF-specific responses in vascular SMC.

Highlights

Growth and migration of vascular smooth muscle cells (VSMC)1 are critical events in the pathogenesis of atherosclerosis, hypertension, and angiogenesis [1]
The induction of JE mRNA by platelet-derived growth factor (PDGF) appears to be independent of activation of protein kinase C, mobilization of intracellular calcium, or stimulation of the Naϩ-Hϩ exchanger, signals shared by angiotensin II (Ang) and PDGF and often involved in the induction of immediate early genes in SMC [19]
PDGF BB Stimulates JE Transcription in Rat Aortic SMC—To verify that the accumulation of JE mRNA in response to PDGF was due in part to stimulation of transcription, nuclear run-on assays were performed (Fig. 1)

Summary

Introduction

Growth and migration of vascular smooth muscle cells (VSMC) are critical events in the pathogenesis of atherosclerosis, hypertension, and angiogenesis [1]. Attempts by this laboratory to identify differences in gene expression in response to Ang and PDGF using differential screening or high resolution two-dimensional protein gels [11, 12] have been unsuccessful, underscoring the similarities in signaling and gene induction between the two agonists These studies suggest that there are a limited number of molecular events that distinguish the hypertrophic and hyperplastic responses of VSMC. In contrast to other cell types, where the induction of JE mRNA is common to a variety of growth agonists, the induction of JE mRNA and chemotactic activity in rat aortic SMC was specific to calf serum and PDGF and was not seen with other agonists, including Ang or ␣-thrombin [19].

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