ALTERED GROWTH CONTROL OF HEPATOCYTES DURING THE CARCINOGENESIS AND ITS REGULATION

癌变过程中肝细胞生长控制的改变及其调控

• 批准号: 09470138
• 负责人: KAWATA Sumio
• 金额: $ 4.61万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470138/
• 关键词: Hepatocellular carcinoma; TGF-b; TGF-b receptor; gene mutation; cell growth

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.

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。

项目成果

K.Fukuda, S.Kawata, et al.: "Transforming growth factor-β induced degradation of actirated Src tyrosine kinase in rat fibroblasts." Oncogene. 16. 3249-3356 (1998)

K.Fukuda、S.Kawata 等人：“转化生长因子-β 诱导大鼠成纤维细胞中活化的 Src 酪氨酸激酶降解。”16. 3249-3356 (1998)

T.Nagase, S.Kawata, et al.: "Effect of farnesyl transferase over expression on cell growth and transformation." Int.J.Cancer. 80. 126-133 (1999)

T.Nagase、S.Kawata 等人：“法呢基转移酶过度表达对细胞生长和转化的影响”。

K.Fukuda, S.Kawata, et al.: "Altered regulation of Src tyrosine kinase by transfoming growth factor-β in a human hepatoma cell line." Hepatology. 28. 796-804 (1998)

K.Fukuda、S.Kawata 等人：“通过转化人肝癌细胞系中的生长因子-β 改变 Src 酪氨酸激酶的调节。”28. 796-804 (1998)。

K.Fukuda, S.Kawata, et al.: "Altered regulation of Src tyrosine kinase by transforming growth factor-b in a human hepatoma cell line." Hepatology. 28. 796-804 (1998)

K.Fukuda、S.Kawata 等人：“通过转化人肝癌细胞系中的生长因子-b 来改变 Src 酪氨酸激酶的调节。”

H.Tsushima, S.Kawata, et al.: "Reduced plasma TGF-β1 levels in patients with chronic hepatitis C after interferon-α." J.Hepatol.30. 1-7 (1999)

H.Tsushima、S.Kawata 等人：“干扰素-α 治疗后慢性丙型肝炎患者血浆 TGF-β1 水平降低。”J.Hepatol.30 (1999)。