Downregulation of Cap43 gene by von Hippel-Lindau tumor suppressor protein in human renal cancer cells.

Abstract

We previously identified 9 genes (i.e., thymosin beta4, secreted protein acidic and rich in cysteine, Cap43, ceruloplasmin, serum amyloid A, heat shock protein 90, LOT1, osteopontin and casein kinase Igamma) that are more highly expressed in cancerous regions than in noncancerous regions in human renal cancers. In our study, we considered the possibility that the von Hippel-Lindau (VHL) tumor suppressor gene might be able to affect the expression of these 9 genes in renal cancer cells. We first established 2 VHL-positive cell lines, 786/VHL-1 and 786/VHL-2, after the introduction of wild-type VHL into VHL-negative renal cancer 786-O cells. Of these 9 genes, expression of the Cap43 gene was specifically downregulated by VHL. Expression of Cap43 was also much lower in 4 other VHL-positive renal cancer cell lines than in VHL-negative 786-O cells. Cap43 promoter assays with several deletion or mutation constructs demonstrated that the Sp1 site in the element from -286 base pairs (bp) to -62 bp was partly responsible for VHL-induced suppression of the Cap43 gene. Immunostaining analysis with human specimens of renal cancers demonstrated that the Cap43 protein was expressed in most cancer cells and macrophages. We also observed a marked and specific increase of Cap43 mRNA levels in response to hypoxia or nickel in all VHL-positive cell lines. Cellular expression of Cap43 mRNA in response to hypoxia or nickel thus is closely associated with VHL gene expression in renal cancer cells. Although the function of the Cap43 protein remains unclear, the expression of Cap43 protein could be a molecular marker closely associated with VHL in renal cancer.

• Authors: Katsuaki Masuda, Mayumi Ono, Masahiro Okamoto, Wataru Morikawa, Michihiro Otsubo, Toshiro Migita, Masazumi Tsuneyoshi, Heiwa Okuda, Taro Shuin, Seiji Naito, Michihiko Kuwano
• Journal: International journal of cancer (Int J Cancer) Vol. 105 Issue 6 Pg. 803-10 (Jul 20 2003) ISSN: 0020-7136 [Print] United States
• PMID: 12767066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Cell Cycle Proteins
• Intracellular Signaling Peptides and Proteins
• N-myc downstream-regulated gene 1 protein
• Proteins
• RNA, Messenger
• Tumor Suppressor Proteins
• Nickel
• Ubiquitin-Protein Ligases
• Von Hippel-Lindau Tumor Suppressor Protein
• Ligases
• VHL protein, human

Topics

• Carcinoma, Renal Cell (genetics, metabolism, pathology)
• Cell Cycle Proteins
• Cell Hypoxia
• Cell Line
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins
• Kidney Neoplasms (genetics, metabolism, pathology)
• Ligases (analysis, metabolism)
• Nickel (pharmacology)
• Promoter Regions, Genetic
• Proteins (genetics, metabolism)
• RNA, Messenger (biosynthesis)
• Transcriptional Activation
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (analysis, metabolism)
• Ubiquitin-Protein Ligases
• Von Hippel-Lindau Tumor Suppressor Protein