Abstract

This renewal proposal focuses on the signal transduction pathways that modulate hepatocyte gene expression and proliferation through site-specific phosphorylations of C/EBP-beta. Preliminary results show that TGF-alpha and phorbol esters/PKC-alpha mediate their effects on hepatocyte proliferation, at least in part, through the activation of ribosomal S6-kinase and phosphorylation of C/EBP-beta on its activation domain. In addition, cachexia and TNF-alpha inhibit albumin transcription, at least in part, throug an oxidative stress/NO cascade resulting in the activation of stress-activated protein (SAP)- kinase and phosphorylation of C/EBP-beta on its basic domain, which abolishes the binding of C/EBP-beta to the albumin enhancer/promoter DNA sequence.
The specific aims are 1) assess the role of phosphorylation on hepatocyte proliferation, 2) examine the modulation of hepatocyte proliferatio in C/EBP-beta mice, 3) examine the regulation of the cell cycle by C/EBP-beta in hepatocytes, 4) assess the role of oxidative stress and NO on C/EBP-beta phosphorylation and inhibition of albumin transcription induced by cachexia an TNF-alpha, 5) examine the modulation of albumin expression in C/EBP-beta transgenic mice, and 6) examine the mechanisms that induce decreased albumin expression in human cachexia.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046971-08
Application #
6176261
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Serrano, Jose
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
8
Fiscal Year
2000
Total Cost
$288,774
Indirect Cost

  Institution

Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161

  Publications

Patchornik, Guy; Munson, Keith; Goldshleger, Rivka et al. (2002) The ATP-Mg2+ binding site and cytoplasmic domain interactions of Na+,K+-ATPase investigated with Fe2+-catalyzed oxidative cleavage and molecular modeling. Biochemistry 41:11740-9
Buck, M; Kim, D J; Houglum, K et al. (2000) c-Myb modulates transcription of the alpha-smooth muscle actin gene in activated hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 278:G321-8
Houglum, K; Buck, M; Kim, D J et al. (1998) TNF-alpha inhibits liver collagen-alpha 1(I) gene expression through a tissue-specific regulatory region. Am J Physiol 274:G840-7
Chojkier, M; Houglum, K; Lee, K S et al. (1998) Long- and short-term D-alpha-tocopherol supplementation inhibits liver collagen alpha1(I) gene expression. Am J Physiol 275:G1480-5
Houglum, K; Venkataramani, A; Lyche, K et al. (1997) A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology 113:1069-73
Lee, K S; Cottam, H B; Houglum, K et al. (1997) Pentoxifylline blocks hepatic stellate cell activation independently of phosphodiesterase inhibitory activity. Am J Physiol 273:G1094-100
Houglum, K; Ramm, G A; Crawford, D H et al. (1997) Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis. Hepatology 26:605-10
Houglum, K; Lee, K S; Chojkier, M (1997) Proliferation of hepatic stellate cells is inhibited by phosphorylation of CREB on serine 133. J Clin Invest 99:1322-8
Buck, M; Chojkier, M (1996) Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J 15:1753-65
Houglum, K; Buck, M; Alcorn, J et al. (1995) Two different cis-acting regulatory regions direct cell-specific transcription of the collagen alpha 1(I) gene in hepatic stellate cells and in skin and tendon fibroblasts. J Clin Invest 96:2269-76

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