Transforming growth factor type beta (TGFbeta) is a bifunctional growth regulator which occurs in many normal animal tissues. It is a potent and non-toxic inhibitor of mitogen-induced DNA synthesis in vitro for rat hepatocytes, which have specific TGFbeta receptors. Hepatocytes from regenerating and carcinogen-altered liver bind less TGFbeta than controls. Its great interest is that very few purified, naturally-occurring growth inhibitors have been so far identified in animal tissues. It is therefore an important growth-controlling candidate molecule. An understanding of how the interactions between TGFbeta and the liver change in normal and neoplastic growth will therefore provide important insights into how the controls on growth are altered in disease states. The long term goal of the proposed work is the elucidation of the mechanism for the inhibitory action of TGFbeta in the liver. The short term aim is to investigate the first step in the interaction of TGFbeta with its hepatocyte receptor, to characterize the changes in this interaction induced by chemical hepatocarcinogens and growth stimulation, and to initiate studies on the inhibitory mechanism. It is proposed to study hepatocytes in vitro from quiescent, regenerating and hepatocarcinogen-altered rat liver and hepatoma lines, in order to characterize the normal TGFbeta receptor and how its function changes during normal and neoplastic growth. The effects on the TGFbeta receptor of pH and cell density, regulation by growth factors and portal serum will be studied, as well as receptor internalization and down-regulation. The changes in receptor activity will be correlated with sensitivity to the growth inhibitory effects of TGFbeta. In vivo, TGFbeta gene expression will be measured during normal and neoplastic growth, and the ability of TGFbeta to operate as a growth regulator will be assessed on regenerating liver. To initiate studies on mechanism, the effects of TGFbeta on protein phosphorylation and selective synthesis of candidate inhibitory proteins will be undertaken.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA044602-04
Application #
3458043
Study Section
Pathology B Study Section (PTHB)
Project Start
1988-02-01
Project End
1993-01-31
Budget Start
1990-02-01
Budget End
1991-01-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nishikawa, Y; Wang, M; Carr, B I (1998) Changes in TGF-beta receptors of rat hepatocytes during primary culture and liver regeneration: increased expression of TGF-beta receptors associated with increased sensitivity to TGF-beta-mediated growth inhibition. J Cell Physiol 176:612-23
Nishikawa, Y; Kar, S; Wiest, L et al. (1997) Inhibition of spermidine synthase gene expression by transforming growth factor-beta 1 in hepatoma cells. Biochem J 321 ( Pt 2):537-43
Hasegawa, K; Wang, Z; Inagaki, M et al. (1995) Characterization of a human hepatoma cell line with acquired resistance to growth inhibition by transforming growth factor beta 1 (TGF-beta 1). In Vitro Cell Dev Biol Anim 31:55-61
Polimeno, L; Azzarone, A; Zeng, Q H et al. (1995) Cell proliferation and oncogene expression after bile duct ligation in the rat: evidence of a specific growth effect on bile duct cells. Hepatology 21:1070-8
Inagaki, M; Wang, Z; Carr, B I (1994) Transforming growth factor beta 1 selectively increases gene expression of the serine/threonine kinase receptor 1 (SKR1) in human hepatoma cell lines. Cell Struct Funct 19:305-13
Francavilla, A; Zeng, Q; Polimeno, L et al. (1994) Small-for-size liver transplanted into larger recipient: a model of hepatic regeneration. Hepatology 19:210-6
Inagaki, M; Moustakas, A; Lin, H Y et al. (1993) Growth inhibition by transforming growth factor beta (TGF-beta) type I is restored in TGF-beta-resistant hepatoma cells after expression of TGF-beta receptor type II cDNA. Proc Natl Acad Sci U S A 90:5359-63
Furuya, T; Murase, N; Nakamura, K et al. (1992) Preformed lymphocytotoxic antibodies: the effects of class, titer and specificity on liver vs. heart allografts. Hepatology 16:1415-22
Francavilla, A; Starzl, T E; Carr, B et al. (1991) The effects of FK 506, cyclosporine, and rapamycin on liver growth in vitro and in vivo. Transplant Proc 23:2817-20
Carr, B I; Huang, T H; Itakura, K et al. (1989) TGF beta gene transcription in normal and neoplastic liver growth. J Cell Biochem 39:477-87

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