TGFB RECEPTORS IN HEPATOCARCINOGENESIS

转化生长因子β(TGFbeta)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 是一种有效的、无毒的有丝分裂原诱导的DNA抑制剂 大鼠肝细胞的体外合成，具有特异性 转化生长因子β受体。再生的肝细胞和 致癌物改变的肝脏与转化生长因子β的结合比对照组少。它的 最令人感兴趣的是，很少有纯化的、自然产生的 到目前为止，已经在动物组织中发现了生长抑制物。它 因此是一个重要的生长控制候选分子。 理解转化生长因子β和转化生长因子β之间的相互作用 肝脏在正常生长和肿瘤生长中的变化将因此而 提供有关如何控制增长的重要见解 在疾病状态下改变的。 拟议工作的长期目标是阐明 转化生长因子β在肝脏中抑制作用的机制。这个 短期目标是研究人类与人类相互作用的第一步 转化生长因子β及其肝细胞受体，以表征 化学致癌物诱导的这种相互作用的变化 和生长刺激，并启动抑制作用的研究 机制。 建议从静止期、静止期、 再生和致癌物改变的大鼠肝和肝癌 为了鉴定正常的转化生长因子β受体和 在正常和肿瘤生长过程中其功能是如何变化的。 PH和细胞密度对转化生长因子β受体的影响 将研究生长因子和门静脉血清的调节作用，如 以及受体内化和下调。这个 受体活性的变化将与对 转化生长因子β的生长抑制作用。在体内，转化生长因子β基因 将测量正常和肿瘤生长过程中的表达， 而TGFbeta作为增长调节器运行的能力将 对再生肝进行评估。启动对…的研究 转化生长因子β对蛋白质磷酸化的影响及其机制 并选择性地合成候选抑制蛋白 承担了。

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.