Expression of low molecular G protein Rho family in renal cell carcinoma

低分子G蛋白Rho家族在肾细胞癌中的表达

• 批准号: 13671682
• 负责人: TSUJI Yuji
• 金额: $ 2.18万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671682/
• 关键词: renal cell carcinoma; molecular biology; low molecular G protein; actin cytoskeleton; salt-tolerant protein(STP); 低分子量G蛋白質; Rhoファミリー; Cdc42; 腎癌

Renal cell carcinoma (RCC), a human kidney cancer from the proximal tubular epithelium, accounts for about 3% of adult malignancies. RCC are highly malignant tumors and often spread beyond the kidney. Several factors that may contribute to the process of malignant cell transformation in RCC have previously been characterized, and include cigarette smoking, obesity, hypertension, chemical agents, genetics and end-stage renal disease. The development of RCC from normal renal epithelium may involve alterations in genes, such as VHL, p53 and Ras, whose products control cell division. However, the pathogenic mechanisms that promote tumor progression, invasion and metastasis, have not yet been defined.The Rho family is a subgroup of the Ras superfamily, in which the RhoA, Rac1 and Cdc42 proteins have been most extensively characterized. They play an essential role in the organization of the actin cytoskeleton and cell adhesion, as well as proliferation, gene expression, and cell cycle regula … More tion. We have isolated a novel human cDNA coding for human salt-tolerant protein (HSTP), which is a homologue of the rat salt-tolerant protein (STP). STP is localized mainly in the proximal tubules, is induced by high-salt loading, and somehow interacts with intracellular cation homeostasis. The nucleotide sequence (1988bp) of the HSTP cDNA contains an open reading frame encoding a polypeptide that consist of 545 amino acids and shows a high degree (98%) of nucleotide identity to human CIP4, which binds specifically to the active GTP-bound conformation of Cdc42. We report here that we have identified a mutation in the HSTP gene in patients with renal cell carcinoma (RCC); fifty percent (15 of 29) of RCCs examined showed an aberrant splicing event in reverse transcription (RT)-PCR and the insertion of 19 nucleotides derived from intron9 in a sequence analysis. This mutant encodes a premature stop codon, resulting in loss of the SH3 domain and Cdc42 binding domain. HSTP may be involved in the tumorigenesis and invasiveness of RCC, probably through its effects on the actin cytoskeleton. Less

肾细胞癌（RCC）是一种来自近端小管上皮的人类肾癌，约占成人恶性肿瘤的3%。肾细胞癌是高度恶性肿瘤，常扩散到肾脏以外。有几个因素可能有助于肾癌恶性细胞转化的过程，包括吸烟、肥胖、高血压、化学制剂、遗传和终末期肾病。从正常肾上皮发展成肾细胞癌可能涉及基因的改变，如VHL、p53和Ras，这些基因的产物控制细胞分裂。然而，促进肿瘤进展、侵袭和转移的致病机制尚未明确。Rho家族是Ras超家族的一个亚群，其中RhoA， Rac1和Cdc42蛋白被广泛表征。它们在肌动蛋白骨架的组织和细胞粘附、增殖、基因表达、细胞周期调节等方面发挥着重要作用。我们分离出一种新的人类耐盐蛋白（HSTP）的cDNA编码，它是大鼠耐盐蛋白（STP）的同源物。STP主要定位于近端小管，由高盐负荷诱导，并以某种方式与细胞内阳离子稳态相互作用。HSTP cDNA的核苷酸序列（1988bp）包含一个开放阅读框，编码一个由545个氨基酸组成的多肽，与人类CIP4具有高度（98%）的核苷酸一致性，特异性结合Cdc42的活性gtp结合构象。我们在这里报告，我们已经确定在肾细胞癌（RCC）患者HSTP基因突变；50%的rcc（29个中的15个）在逆转录(RT)-PCR中显示了异常剪接事件，并且在序列分析中插入了来自内含子9的19个核苷酸。该突变体编码一个过早终止密码子，导致SH3结构域和Cdc42结合结构域的丢失。HSTP可能通过其对肌动蛋白细胞骨架的影响参与了RCC的肿瘤发生和侵袭。少

项目成果

Tsuji, Y, Tsuji, E: "Human salt-tolerant protein alternativesplicing mutation in renal cell carcinoma"Cancer Research. (submitted).

Tsuji，Y，Tsuji，E：“肾细胞癌中的人类耐盐蛋白替代剪接突变”癌症研究。

Tsuji Y & Tsuji E: "Human Cdc42 interacting protein alternative splicing mutation in renal cell carcinoma"Cancer research. (submitted).

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