The von Hippel-Lindau (VHL) syndrome is a hereditary syndrome that predisposes affected patients to develop a variety of neoplasms including sporadic renal cell carcinomas, pheochromocytomas, and CNS hemangioblastomas. VHL-associated neoplasms are typically hypervascular and overproduce angiogenic peptides, such as vascular endothelial growth factor (VEGF), probably because the VHL gene product (pVHL) is a negative regulator of hypoxia-inducible mRNAs. pVHL is also known to form a complex (hCul-2-VBC) with human cullin-2 (hCul-2) through elongins B/C and possesses a tumor suppressor function in vivo. Interestingly, a frequently mutated region of pVHL in patients with VHL syndrome contains a binding site for elongins B/C and the mutations interfere with the formation of the hCul-2-VBC complex, suggesting that the inability to form the hCul-2-VBC complex plays a critical role in the pathogenesis of VHL syndrome. Recently, we found that hCul-2 is covalently modified by a single molecule of NEDD8, a novel ubiquitin-like protein which does not target proteins for proteolytic degradation by proteasome. This post-translational modification of hCul-2 by NEDD8 may regulate the formation or the function of the hCul-2- VBC complex. This proposal is designed to study the mechanism and biological function of NEDD8-modification, using hCul-2 as a model substrate. In particular, we will focus on the role of NEDD8- conjugation in the pathogenesis of VHL syndrome.
The aims are to define: 1) the target Lys residue of hCul-2 which is covalently modified by NEDD8, 2) the relationship between phosphorylation and NEDD8-conjugation of hCul-2, 3) the effect of NEDD8- conjugation to hCul-2 on cell-cycle progression, 4) the role of NEDD8-conjugation to hCul-2 in the formation and subcellular localization of hCul-2-VBC complex and in the regulation of hypoxia-inducible mRNA, such as VEGF.
| Tanaka, Tomoaki; Nakatani, Tatsuya; Kamitani, Tetsu (2013) Negative regulation of NEDD8 conjugation pathway by novel molecules and agents for anticancer therapy. Curr Pharm Des 19:4131-9 |
| Tanaka, Tomoaki; Nakatani, Tatsuya; Kamitani, Tetsu (2012) Inhibition of NEDD8-conjugation pathway by novel molecules: potential approaches to anticancer therapy. Mol Oncol 6:267-75 |
| Wada, Keiji; Niida, Motoko; Tanaka, Makoto et al. (2009) Ro52-mediated monoubiquitination of IKK{beta} down-regulates NF-{kappa}B signalling. J Biochem 146:821-32 |
| Yamauchi, Keiko; Wada, Keiji; Tanji, Kunikazu et al. (2008) Ubiquitination of E3 ubiquitin ligase TRIM5 alpha and its potential role. FEBS J 275:1540-55 |
| Wada, Keiji; Tanji, Kunikazu; Kamitani, Tetsu (2006) Function and subcellular location of Ro52beta. Biochem Biophys Res Commun 340:872-8 |
| Wada, Keiji; Kamitani, Tetsu (2006) Autoantigen Ro52 is an E3 ubiquitin ligase. Biochem Biophys Res Commun 339:415-21 |
| Tanji, Kunikazu; Tanaka, Tomoaki; Mori, Fumiaki et al. (2006) NUB1 suppresses the formation of Lewy body-like inclusions by proteasomal degradation of synphilin-1. Am J Pathol 169:553-65 |
| Wada, Keiji; Tanji, Kunikazu; Kamitani, Tetsu (2006) Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity. Biochem Biophys Res Commun 339:731-6 |
| Wada, Keiji; Kamitani, Tetsu (2006) UnpEL/Usp4 is ubiquitinated by Ro52 and deubiquitinated by itself. Biochem Biophys Res Commun 342:253-8 |
| Tanji, Kunikazu; Tanaka, Tomoaki; Kamitani, Tetsu (2005) Interaction of NUB1 with the proteasome subunit S5a. Biochem Biophys Res Commun 337:116-20 |
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