title: A phospholipase Cγ1-activated pathway regulates transcription in human vascular smooth muscle cells.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  In cultured human VSM cells, phospholipase C (PLC)γ1 expression was required for platelet-derived growth factor (PDGF)-induced ERK1/2 nuclear translocation, Elk-1 phosphorylation, and subsequent repression of SM α-actin gene expression. The mechanisms of a role for PLCγ1 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 PLCγ1. In cells pre-treated with PEA-15 siRNA, ERK1/2 distribution significantly increased in the nucleus and resulted in decreased SM α-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.
  
  
  CONCLUSIONS
  These results suggest that PEA-15 phosphorylation by PLCγ1 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.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Hunter
authors.forename: Keith S
authors.initials: KS
authors.lastname: Mascall
authors.forename: Joe W
authors.initials: JW
authors.lastname: Ramos
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Nixon
mesh_terms: D000199:Actins / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D051017:Apoptosis Regulatory Proteins; D000077214:Becaplermin; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D051017:Apoptosis Regulatory Proteins; C494112:ELK1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D050807:ets-Domain Protein Elk-1; D000077214:Becaplermin; D051966:Phospholipase C gamma