Hepatocyte growth factor signaling regulates transactivation of genes belonging to the plasminogen activation system via hypoxia inducible factor-1.
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.
Institute of General Pathology, University of Milano, via L. Mangiagalli, 31, 20133 Milano, Italy.
Lorenza
L
Tacchini
Emanuela
E
Matteucci
Cristina
C
De Ponti
Maria Alfonsina
MA
Desiderio
D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D016758:Genes, jun / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator