Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound

Mol Cell Biol. 2002 Aug;22(15):5492-505. doi: 10.1128/mcb.22.15.5492-5505.2002.

Abstract

Keratinocyte growth factor (KGF) is a potent mitogen for epithelial cells, and it promotes survival of these cells under stress conditions. In a search for KGF-regulated genes in keratinocytes, we identified the gene encoding the transcription factor NF-E2-related factor 2 (Nrf2). Nrf2 is a key player in the cellular stress response. This might be of particular importance during wound healing, where large amounts of reactive oxygen species are produced as a defense against invading bacteria. Therefore, we studied the wound repair process in Nrf2 knockout mice. Interestingly, the expression of various key players involved in wound healing was significantly reduced in early wounds of the Nrf2 knockout animals, and the late phase of repair was characterized by prolonged inflammation. However, these differences in gene expression were not reflected by obvious histological abnormalities. The normal healing rate appears to be at least partially due to an up-regulation of the related transcription factor Nrf3, which was also identified as a target of KGF and which was coexpressed with Nrf2 in the healing skin wound. Taken together, our results reveal novel roles of the KGF-regulated transcription factors Nrf2 and possibly Nrf3 in the control of gene expression and inflammation during cutaneous wound repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors
  • Blotting, Western
  • Cell Line
  • Cytokines / metabolism
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Fibroblast Growth Factor 7
  • Fibroblast Growth Factors / pharmacology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1
  • Humans
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Membrane Proteins
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • NF-E2-Related Factor 2
  • Oxidative Stress
  • RNA, Messenger / metabolism
  • Skin / drug effects
  • Skin / injuries*
  • Skin / pathology
  • Trans-Activators / deficiency
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Wound Healing* / drug effects
  • Wound Healing* / physiology

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Cytokines
  • DNA-Binding Proteins
  • FGF7 protein, human
  • Fgf7 protein, mouse
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • NFE2L3 protein, human
  • Nfe2l2 protein, mouse
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factors
  • Fibroblast Growth Factor 7
  • Fibroblast Growth Factors
  • HMOX1 protein, human
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • Glutathione Transferase