A phospholipase Cγ1-activated pathway regulates transcription in human vascular smooth muscle cells

Irene Hunter, Keith Stewart Mascall, Joe Ramos, Graeme Fleming Nixon (Corresponding Author)

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Aims Growth factor-induced repression of smooth muscle (SM) cell marker genes is an integral part of vascular SM (VSM) cell proliferation. This is partly regulated via translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) to the nucleus which activates the transcription factor Elk-1. The mediators involved in ERK1/2 nuclear translocation in VSM cells are unknown. The aim of this study is to examine the mechanisms which regulate growth factor-induced nuclear translocation of ERK1/2 and gene expression in VSM cells.
Methods and results In cultured human VSM cells, phospholipase C (PLC)¿1 expression was required for platelet-derived growth factor (PDGF)-induced ERK1/2 nuclear translocation, Elk-1 phosphorylation, and subsequent repression of SM a-actin gene expression. The mechanisms of a role for PLC¿1 in ERK1/2 nuclear localization were further examined by investigating interacting proteins. The ERK1/2-binding phosphoprotein, protein enriched in astrocytes-15 (PEA-15), was phosphorylated by PDGF and this phosphorylation required activation of PLC¿1. In cells pre-treated with PEA-15 siRNA, ERK1/2 distribution significantly increased in the nucleus and resulted in decreased SM a-actin expression and increased VSM cell proliferation. Overexpression of PEA-15 increased ERK1/2 localization in the cytoplasm. The regulatory role of PEA-15 phosphorylation was assessed. In VSM cells overexpressing a non-phosphorylatable form of PEA-15, PDGF-induced ERK1/2 nuclear localization was inhibited.
Conclusion These results suggest that PEA-15 phosphorylation by PLC¿1 is required for PDGF-induced ERK1/2 nuclear translocation. This represents an important level of phenotypic control by directly affecting Elk-1-dependent transcription and ultimately SM cell marker protein expression in VSM cells.
Original languageEnglish
Pages (from-to)557-564
Number of pages8
JournalCardiovascular Research
Volume90
Issue number3
DOIs
Publication statusPublished - 1 Jun 2011

    Fingerprint

Keywords

  • Vascular smooth muscle
  • Phospholipase C
  • Transcription
  • Mitogen-activated protein kinase

Cite this