Transcription factor activation and mitogenic synergism in airway smooth muscle cells

Simultaneous treatment of human airway smooth muscle (HASM) cells with lysophosphatidic 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, focusi...

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Bibliographic Details
Published in:	The European respiratory journal Vol. 21; no. 5; pp. 759 - 769
Main Authors:	Ediger, T.L, Schulte, N.A, Murphy, T.J, Toews, M.L
Format:	Journal Article
Language:	English
Published:	Leeds Eur Respiratory Soc 01-05-2003 Maney
Subjects:	Acute-Phase Proteins - metabolism Air breathing Biological and medical sciences Botulinum Toxins - pharmacology Cell Transformation, Neoplastic - drug effects Cell Transformation, Neoplastic - metabolism Cells, Cultured Epidermal Growth Factor - pharmacology Fundamental and applied biological sciences. Psychology Humans Lysophospholipids - pharmacology MAP Kinase Signaling System - physiology Mitogens - metabolism Myocytes, Smooth Muscle - metabolism Myocytes, Smooth Muscle - pathology Respiratory system: anatomy, metabolism, gas exchange, ventilatory mechanics, respiratory hemodynamics Trachea Transcription Factor AP-1 - metabolism Transcription Factors - metabolism Vertebrates: respiratory system Human Extracellular signal-regulated protein kinase Activator protein-1 asthma growth factors nuclear factor-κB proliferation Rho Enzyme Respiratory system Synergism Biological activity Myocyte Respiratory tract Epidermal growth factor Lysophosphatidic acid Mitogen Transcription factor NFκB Transcription factor AP1
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Summary:	Simultaneous treatment of human airway smooth muscle (HASM) cells with lysophosphatidic 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)-kappaB was activated by LPA but not EGF and NF-kappaB 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.
ISSN:	0903-1936 1399-3003
DOI:	10.1183/09031936.03.00075702