TGFB RECEPTORS IN HEPATOCARCINOGENESIS

转化生长因子β（TGF β）是一种双功能的 生长调节剂，存在于许多正常动物组织中。 它 是有丝分裂原诱导DNA的有效和无毒抑制剂 体外合成大鼠肝细胞，其具有特异性 TGF β受体。 再生的肝细胞， 致癌物改变的肝脏比对照组结合更少的TGF β。 其 很大的兴趣是，很少有纯化的，自然发生的， 迄今为止已经在动物组织中鉴定出生长抑制剂。 它 因此是重要的生长控制候选分子。 了解TGF β和 因此，正常和肿瘤生长中的肝脏变化将 提供了关于如何控制增长的重要见解， 改变疾病状态。 拟议工作的长期目标是阐明 肝脏中TGF β抑制作用的机制。 的 短期目标是研究相互作用的第一步， TGF β及其肝细胞受体，以表征 化学致癌物引起的这种相互作用的变化 和生长刺激，并启动抑制研究， 机制 建议在体外研究来自静止期的肝细胞， 大鼠肝再生和肝癌 线，以表征正常的TGF β受体和 在正常和肿瘤生长过程中其功能如何变化。 pH和细胞密度对TGF β受体的影响， 将研究生长因子和门静脉血清的调节， 以及受体内化和下调。 的 受体活性的变化将与对 TGF β的生长抑制作用。 体内，TGF β基因 在正常和肿瘤生长期间测量表达， 而TGF β作为生长调节剂的能力 评估再生肝脏。 启动关于 TGF β对蛋白质磷酸化的影响 并且选择性合成候选抑制蛋白将是 进行。

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.