| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
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
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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
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