ALTERED GROWTH CONTROL OF HEPATOCYTES DURING THE CARCINOGENESIS AND ITS REGULATION

我们正在研究在癌变过程中改变对肝细胞生长的控制。改变的调节似乎来自于通过肝细胞反应性的丧失从TGF-β的负生长控制中逃脱。为探讨Src激酶是否参与TGF-β信号转导，我们检测了TGF-β_1对大鼠成纤维细胞系3Y_1和转化为Src的SR-3Y_1中Src的影响。TGF-β_1抑制SR-3Y_1细胞的MAP激酶活性，抑制细胞生长，但对3Y_1细胞生长无影响。TGF-β 1显著降低SR-3 Y1细胞v-Src激酶活性和蛋白质丰度，主要是通过加速v-Src的降解。相反，在3 Y1细胞中，TGF-β 1不影响c-Src的丰度或激酶活性。然而，在PDGF激活3 Y1细胞中的c-Src后，TGF-β 1降低Src丰度。此外，在用缺乏SH 3结构域的活化的c-Src突变体转染的3 Y1细胞中，其水平通过TGF-β 1处理而降低。这些发现表明，TGF-β 1特异性诱导活化的Src激酶的降解。这可能是生长因子和TGF-β之间相互作用的一种新机制。

We are studying on altered control on hepatocytes growth during the carcinogensis. The altered regulation seems to be derived from escape from negative growth control by TGF-b via , a loss of responsivity of hepatocytes. Our hypothesis is that ther is not only defect of TGF-b receptor but also alteration of the signal transduction pathway of the cytokine.To determined wether Src kinase is involved in TGF-b signaling, we examined the effects of TGF-b1 on Src in rat fibroblast- cell line 3Y1 and in v-Src-transformed 3Y1 (SR-3Y1). TGF-b1 inhibited MAP kinase activity and inhibited growth in SR-3Y1 cells, while it did not affect the growth of 3Y1 cells. TGF-b1 significantly decreased v-Src kinase activity and protein abundance in SR-3Y1 cells, mainly by accelerating the degradation of v-Src. In contrast, in 3Y1 cells, TGF-b1 did not affect c-Src abandance or kinase activity. however, upon activation of c-Src in 3Y1 cells by PDGF, TGF-b1 decreased Src abundance. Additionally, in 3Y1 cells transfected with an activated c-Src mutant which lacks the SH3 domain, its level was decreased by TGF-b1 treatment. These findings suggest that TGf-b1 specifically induces degradation of activated Src kinase. This may be a novel mechanism for cross-talk between growth factors and TGF-b.