Transcription factor activation and mitogenic synergism in airway smooth muscle cells

T. L. Ediger, N. A. Schulte, T. J. Murphy, M. L. Toews

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Simultaneous treatment of human airway smooth muscle (HASM) cells with lysophoshatidic acid (LPA) and epidermal growth factor (EGF) leads to strikingly synergistic stimulation of mitogenesis. The purpose of this study was to explore potential sites for signal integration mediating synergism, focusing on extracellular signal-regulated kinase (ERK) and transcription factors involved in proliferation and inflammation as likely candidates. Activation of ERK was analysed by immunoblotting. Transcription factor activation was assessed using HASM cells transduced with luciferase reporter gene constructs. LPA and EGF both activated ERK but had no synergistic effect when combined. LPA and EGF both activated activator protein (AP)-1, cyclic adenosine monophosphate response element-binding protein, nuclear factor of activated T-cells and the serum response element; however, only AP-1 activation exhibited synergism. Activation of the inhibitory guanine nucleotide-binding protein and of ERK signalling pathways were required for most transcription factor responses to LPA. In contrast, nuclear factor (NF)-κB was activated by LPA but not EGF and NF-κB activation was completely blocked only when Rho was inhibited. Rapid activation of Rho was observed in response to LPA but not to EGF. Importantly, inhibition of Rho selectively blocked synergism in both AP-1 activation and mitogenesis. In summary, extracellular signal-regulated kinase activation is required for many transcription factor responses to lysophosphatidic acid and epidermal growth factor, however it is not synergistic. Activation of activator protein-1 is synergistic, and Rho activation by lysophosphatidic acid is required for synergism in both activator protein-1 activation and mitogenesis.

Original languageEnglish (US)
Pages (from-to)759-769
Number of pages11
JournalEuropean Respiratory Journal
Volume21
Issue number5
DOIs
StatePublished - May 1 2003

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Keywords

  • Activator protein-1
  • Asthma
  • Growth factors
  • Nuclear factor-κB
  • Proliferation
  • Rho

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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