Insulin-like growth factor-II regulates the expression of vascular endothelial growth factor by the human keratinocyte cell line HaCaT

J Invest Dermatol. 2004 Jul;123(1):152-8. doi: 10.1111/j.0022-202X.2004.22735.x.

Abstract

Psoriasis is a chronic, relapsing skin disease characterized by enhanced angiogenesis. The pathogenetic process resulting in hypervascularity remains to be further investigated. It has been reported that a potent angiogenic factor, vascular endothelial growth factor (VEGF) is overexpressed in psoriatic epidermis and that the level of insulin-like growth factor II (IGF-II) is significantly elevated in the tissue fluid and serum of the psoriatic lesion. We considered the possibility that IGF-II might function as a paracrine inducer of VEGF. Here, we demonstrated that exposure of HaCaT keratinocytes to IGF-II induced both mRNA and protein expression of VEGF through the MAP kinase (extracellular signal-regulated kinase (ERK2) pathway. Particularly, we determined that phosphorylation of ERK2 but not p38 and JNK1/2 was activated by IGF-II in a time-dependent manner. Additionally, we found that IGF-II treatment induced the expression of MDM2 through the MAP kinase pathway. Moreover, the increase of MDM2 resulted in decreased levels of p53 followed by increased expression of HIF-1alpha and VEGF. Taken together, these results suggest that IGF-II enhances the expression of VEGF in HaCaT cells by increasing HIF-1alpha levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Gene Expression / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin-Like Growth Factor II / pharmacology*
  • Keratinocytes / cytology
  • Keratinocytes / physiology*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism
  • Neovascularization, Physiologic / physiology
  • Nuclear Proteins / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • Psoriasis / physiopathology*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation / drug effects
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Vascular Endothelial Growth Factor A
  • Insulin-Like Growth Factor II
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases