Hepatocyte growth factor signaling regulates transactivation of genes belonging to the plasminogen activation system via hypoxia inducible factor-1

Exp Cell Res. 2003 Nov 1;290(2):391-401. doi: 10.1016/s0014-4827(03)00348-3.


Hepatocyte growth factor (HGF) plays an important role in tumor growth and progression also by regulating invasive/metastatic phenotype and angiogenesis. Here we report that a molecular mechanism possibly contributing to these functions of HGF may be hypoxia inducible factor-1 (HIF-1)-dependent expression of genes of the plasminogen activation system. The following findings support this conclusion: (1) HGF enhanced the activity of a luciferase reporter construct under the control of multiple HIF-1 responsive elements (HRE) in HepG2 cells, and the cotransfection of the dominant negative for the beta-subunit (ARNT) prevented this increase; (2) HGF activated uPA and PAI-1 promoters through HIF-1 activity regulated by PI3K/JNK1 transducers, as demonstrated by cotransfection with the reporter gene promoters and the dominant negative for ARNT, p85 subunit of PI3K or JNK1; (3) hypoxia was additive to HGF in increasing reporter vector activities, but probably through different transduction pathways; (4) JNK1 wild-type expression vector increased HIF-1alpha protein expression probably in a phosphorylated state and, thus, functional for transactivating activity; and (5) c-Jun did not seem to be involved in the activation of the luciferase construct containing multiple HREs because it was not prevented by expression of TAM-67, which is the dominant negative mutant form for c-Jun.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation
  • Genes, jun / physiology
  • Hepatocyte Growth Factor / physiology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phosphatidylinositol 3-Kinases / physiology
  • Phosphorylation
  • Plasminogen Activator Inhibitor 1 / genetics*
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Plasminogen Activators / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction*
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Urokinase-Type Plasminogen Activator / genetics*
  • Urokinase-Type Plasminogen Activator / metabolism


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Transcription Factors
  • Hepatocyte Growth Factor
  • Phosphatidylinositol 3-Kinases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Plasminogen Activators
  • Urokinase-Type Plasminogen Activator