Abstract

The major aim of the grant is to understand the roles of C/EBP-like transcription factors in the regulation of liver-specific genes using in vitro cell culture model systems and null mutations produced in transgenic animals by homologous recombination strategies. We have characterized an in vitro model of the inflammatory or acute phase response in man using a human hepatoma cell line, Hep 3B2. A subset of the acute phase response genes are transcriptionally regulated by DNA binding proteins of the C/EBP family. Seven family members have been identified that utilize a common consensus element. However, the role of each of these gene products in liver-specific gene regulation during the acute phase and during differentiation is not well understood. We will use null mutants of the Hep 3B2 cells generated by antisense methodologies or homologous recombination to clarify the roles of the individual members of the family. We will clone the full complement of C/EBP-like genes expressed in hepatoma cells and in liver. We will characterize the promoter elements of the C/EBPalpha gene and define cis-elements that influence C/EBPalpha expression. Cis-elements which are regulated by other C/EBP family members will be sought and characterized in detail. Finally, we will examine the role of C/EBPalpha in development and in the acute phase response of mice. For these studies, we will introduce null mutations by homologous recombination in embryonic stem cells to generate animals which are mutant for one or the other of these loci.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045285-02
Application #
2144500
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1993-05-01
Project End
1997-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Linhart, H G; Ishimura-Oka, K; DeMayo, F et al. (2001) C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proc Natl Acad Sci U S A 98:12532-7
Timchenko, N A; Wilde, M; Iakova, P et al. (1999) E2F/p107 and E2F/p130 complexes are regulated by C/EBPalpha in 3T3-L1 adipocytes. Nucleic Acids Res 27:3621-30
Burgess-Beusse, B L; Timchenko, N A; Darlington, G J (1999) CCAAT/enhancer binding protein alpha (C/EBPalpha) is an important mediator of mouse C/EBPbeta protein isoform production. Hepatology 29:597-601
Wu, Z; Rosen, E D; Brun, R et al. (1999) Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 3:151-8
Timchenko, N A; Wilde, M; Kosai, K I et al. (1998) Regenerating livers of old rats contain high levels of C/EBPalpha that correlate with altered expression of cell cycle associated proteins. Nucleic Acids Res 26:3293-9
Oesterreicher, T J; Leeper, L L; Finegold, M J et al. (1998) Intestinal maturation in mice lacking CCAAT/enhancer-binding protein alpha (C/EPBalpha). Biochem J 330 ( Pt 3):1165-71
Kimura, T; Christoffels, V M; Chowdhury, S et al. (1998) Hypoglycemia-associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPalpha knockout mice. J Biol Chem 273:27505-10
Darlington, G J; Ross, S E; MacDougald, O A (1998) The role of C/EBP genes in adipocyte differentiation. J Biol Chem 273:30057-60
Soriano, H E; Kang, D C; Finegold, M J et al. (1998) Lack of C/EBP alpha gene expression results in increased DNA synthesis and an increased frequency of immortalization of freshly isolated mice [correction of rat] hepatocytes. Hepatology 27:392-401
Burgess-Beusse, B L; Darlington, G J (1998) C/EBPalpha is critical for the neonatal acute-phase response to inflammation. Mol Cell Biol 18:7269-77

Showing the most recent 10 out of 16 publications