TGFB RECEPTORS IN HEPATOCARCINOGENESIS

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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.