The fibrotic phenotype induced by IGFBP-5 is regulated by MAPK activation and egr-1-dependent and -independent mechanisms. Academic Article uri icon

Overview

MeSH

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Cell Movement
  • Cell Nucleus
  • Enzyme Activation
  • Fibronectins
  • Humans
  • Mice
  • Mice, Knockout
  • Transcription, Genetic

MeSH Major

  • Early Growth Response Protein 1
  • Insulin-Like Growth Factor Binding Protein 5
  • Mitogen-Activated Protein Kinase Kinases
  • Pulmonary Fibrosis

abstract

  • We have previously shown that insulin-like growth factor (IGF) binding protein- 5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that IGFBP-5 induction of extracellular matrix occurs independently of IGF-I, and results from IGFBP-5 activation of MAPK signaling, which facilitates the translocation of IGFBP-5 to the nucleus. We examined the effects of IGFBP-5 on early growth response (Egr)-1, a transcription factor that is central to growth factor-mediated fibrosis. Egr-1 was up-regulated by IGFBP-5 in a MAPK-dependent manner and bound to nuclear IGFBP-5. In fibroblasts from Egr-1 knockout mice, induction of fibronectin by IGFBP-5 was abolished. Expression of Egr-1 in these cells rescued the extracellular matrix-promoting effects of IGFBP-5. Moreover, IGFBP-5 induced cell migration in an Egr-1-dependent manner. Notably, Egr-1 levels, similar to IGFBP-5, were increased in vivo in lung tissues and in vitro in primary fibroblasts of patients with pulmonary idiopathic fibrosis. Taken together, our findings suggest that IGFBP-5 induces a fibrotic phenotype via the activation of MAPK signaling and the induction of nuclear Egr-1 that interacts with IGFBP-5 and promotes fibrotic gene transcription.

publication date

  • August 2009

has subject area

  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line
  • Cell Movement
  • Cell Nucleus
  • Early Growth Response Protein 1
  • Enzyme Activation
  • Fibronectins
  • Humans
  • Insulin-Like Growth Factor Binding Protein 5
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases
  • Pulmonary Fibrosis
  • Transcription, Genetic

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2716960

Digital Object Identifier (DOI)

  • 10.2353/ajpath.2009.080991

PubMed ID

  • 19628764

Additional Document Info

start page

  • 605

end page

  • 615

volume

  • 175

number

  • 2