Regulation of endothelin receptor expression through cancer cell differentiation

通过癌细胞分化调节内皮素受体表达

• 批准号: 10670084
• 负责人: NINOMIYA Haruaki
• 金额: $ 2.18万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670084/
• 关键词: endothelin; receptor; cancer; melanoma; apoptosis; Niemann-Pick; cholesterol; カベオラ; コレステロール; がん

In the current study, we focused on the ET-1-activated signal transduction pathways in cancer cells and found that ET-1, via activation of ETB receptors, induced expression of p53 and apoptotic cell death of A375 melanoma cells. There was a threshold value of ETB receptor densities expressed by individual cells to induce these responses and the receptor densities were controlled by a cell-cycle-dependent manner. We also found that ET-1/ETA complexes can be internalized both via clathrin-coated pits and caveolae and that the pathway selection was controlled by cholesterol contents of the plasma membrane. In relation to the latter finding, we analyzed the function of Niemann-Pick C1 protein that plays a critical role in the maintenance of cellular cholesterol homeostasis. We found that in addition to its critical role in cholesterol outflow from the late endosome, NPC1 protein is involved in the transport of GM1 ganglioside from the early endosome to the plasma membrane. This finding suggested that the internalization of ET-1/ETA complexes could be controlled by NPC1 in an indirect manner. Thus, the current study gave new insights both to the ET-1-induced signal transduction and the internalization mechanism of ET-1/receptor complexes.

在本研究中，我们重点关注癌细胞中ET-1激活的信号转导通路，发现ET-1通过激活ETB受体，诱导p53的表达和A375黑色素瘤细胞的凋亡。单个细胞表达的 ETB 受体密度存在一个阈值来诱导这些反应，并且受体密度由细胞周期依赖性方式控制。我们还发现 ET-1/ETA 复合物可以通过网格蛋白包被的小凹和小窝内化，并且途径选择由质膜的胆固醇含量控制。关于后一个发现，我们分析了 Niemann-Pick C1 蛋白的功能，该蛋白在维持细胞胆固醇稳态中发挥着关键作用。我们发现，NPC1 蛋白除了在胆固醇从晚期内体流出中发挥关键作用外，还参与 GM1 神经节苷脂从早期内体到质膜的转运。这一发现表明 ET-1/ETA 复合物的内化可以由 NPC1 以间接方式控制。因此，当前的研究为 ET-1 诱导的信号转导和 ET-1/受体复合物的内化机制提供了新的见解。

项目成果

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Yamamoto 等人：“日本结节性硬化症患者中的新型 TSC1 和 TSC2 突变”Brain Dev..（出版中）。

Hosokawa et al.: "Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain"Brain Res.. 838. 158-165 (1999)

Hosokawa 等人：“成年大鼠脑中阳离子氨基酸转运蛋白 3 的神经元特异性表达”Brain Res.. 838. 158-165 (1999)

Nagata K., Yamamoto T., Chikumi H., Ikeda T., Yamamoto H., Hashimoto K., Yoneda K., Nanba E., Ninomiya H. and Ishitobi K.: "A novel interstitial deletion of KAL1 in a Japanese family with Kallmann syndrome"J. Hum. Genet.. 45. 237-240 (2000)

Nagata K.、Yamamoto T.、Chikumi H.、Ikeda T.、Yamamoto H.、Hashimoto K.、Yoneda K.、Nanba E.、Ninomiya H. 和 Ishitobi K.：“日语中 KAL1 的新颖间隙缺失

Chikumi H. et al.: "Fibrillin gene(FBN1)mutations in Japanese patients with Marfan syndrome."J.Hum.Genet.. 45. 115-118 (2000)

Chikumi H. 等人：“日本马凡综合征患者的原纤维蛋白基因 (FBN1) 突变。”J.Hum.Genet.. 45. 115-118 (2000)

Sugimoto Y., Ninomiya H., Ohsaki Y., Higaki K., Davies J.P., Ioannou Y.A. and Ohno K.: "Accumulation of cholera toxin and GM1 ganglioside in the early endosome of Niemann-Pick C1-deficient cells"Proc. Natl. Acad. Sci. USA, 98. 12391-12396 (2001)

杉本 Y.、二宫 H.、Ohsaki Y.、Higaki K.、戴维斯 J.P.、Ioannou Y.A.