Abstract

The overall objective of this renewal proposal is to determine the molecular basis of hepatocyte growth factor (HGF) gene transcription and its function in normal tissue development and tumorigenesis. The first specific aim is to functionally map the regulatory DNA elements in the HGF gene promoter and to characterize the cognate binding proteins that govern HGF gene transcription in a cell-type specific manner in the liver. The second specific aim is to use HGF overexpressing transgenic mice to unravel the mechanisms by which HGF contributes to liver growth and neoplastic transformation. The third specific aim is to produce a transgenic mouse that expresses a recombinant HGF antagonist in the liver to study its effects on normal liver growth and differentiation and hepatocarcinogenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES006109-07
Application #
2838211
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1996-12-01
Project End
2001-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Ma, Jihong; DeFrances, Marie C; Zou, Chunbin et al. (2009) Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer. J Clin Invest 119:478-91
Zhao, Yongge; Difrancesca, Daniell; Wang, Xue et al. (2007) Promotion of Fas-mediated apoptosis in Type II cells by high doses of hepatocyte growth factor bypasses the mitochondrial requirement. J Cell Physiol 213:556-63
Jiang, J G; Johnson, C; Zarnegar, R (2001) Peroxisome proliferator-activated receptor gamma-mediated transcriptional up-regulation of the hepatocyte growth factor gene promoter via a novel composite cis-acting element. J Biol Chem 276:25049-56
Jiang, J G; Gao, B; Zarnegar, R (2000) The concerted regulatory functions of the transcription factors nuclear factor-1 and upstream stimulatory factor on a composite element in the promoter of the hepatocyte growth factor gene. Oncogene 19:2786-90
Jiang, J G; DeFrances, M C; Machen, J et al. (2000) The repressive function of AP2 transcription factor on the hepatocyte growth factor gene promoter. Biochem Biophys Res Commun 272:882-6
Bell, A; Chen, Q; DeFrances, M C et al. (1999) The five amino acid-deleted isoform of hepatocyte growth factor promotes carcinogenesis in transgenic mice. Oncogene 18:887-95
Bell, A W; Jiang, J G; Chen, Q et al. (1998) The upstream regulatory regions of the hepatocyte growth factor gene promoter are essential for its expression in transgenic mice. J Biol Chem 273:6900-8
Jiang, J G; Bell, A; Liu, Y et al. (1997) Transcriptional regulation of the hepatocyte growth factor gene by the nuclear receptors chicken ovalbumin upstream promoter transcription factor and estrogen receptor. J Biol Chem 272:3928-34
Jiang, J G; Chen, Q; Bell, A et al. (1997) Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors. Oncogene 14:3039-49
Jiang, J G; Zarnegar, R (1997) A novel transcriptional regulatory region within the core promoter of the hepatocyte growth factor gene is responsible for its inducibility by cytokines via the C/EBP family of transcription factors. Mol Cell Biol 17:5758-70

Showing the most recent 10 out of 22 publications