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NEDD8-MODIFICATION IN VON HIPPEL-LINDAU SYNDROME

NEDD8-MODIFICATION IN VON HIPPEL-LINDAU SYNDROME
冯·希佩尔-林道综合征中的 NEDD8 修饰
批准号:
6381621
负责人:
TETSU KAMITANI
金额:
$24.14万
依托单位国家:
美国
项目类别:
财政年份:
1999
资助国家:
美国
项目状态:
已结题
起止时间:
1999-08-01 至 2004-07-31

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中文摘要
翻译
Von Hippel-Lindau综合征(VHL)是一种易患多种肿瘤的遗传性综合征,包括散发性肾细胞癌、嗜铬细胞瘤和中枢神经系统血管母细胞瘤。VHL相关肿瘤通常是多血管和过度产生血管生成多肽,如血管内皮生长因子(VEGF),可能是因为VHL基因产物(PVHL)是低氧诱导的mRNAs的负调节因子。PVHL还通过细长蛋白B/C与人cullin-2(hCul-2)形成复合物(hCul-2-VBC),在体内具有肿瘤抑制功能。有趣的是,在VHL综合征患者中,pVHL的一个频繁突变区域含有一个细长蛋白B/C的结合位点,该突变干扰了hCul-2-VBC复合体的形成,这表明无法形成hCul-2-VBC复合体在VHL综合征的发病机制中起着关键作用。最近,我们发现hCul-2被NEDD8的单个分子共价修饰,NEDD8是一种新的泛素样蛋白,不以蛋白酶体降解的蛋白质为靶标。NEDD8对hCul-2的这种翻译后修饰可能调节hCul-2-VBC复合体的形成或功能。本研究以hCul-2为模型底物,对NEDD8修饰的机制和生物学功能进行了研究。特别是,我们将重点介绍NEDD8结合在VHL综合征发病机制中的作用。其目的是确定:1)NEDD8共价修饰的hCul-2的靶Lys残基;2)hCul-2的磷酸化与NEDD8结合的关系;3)NEDD8与hCul-2的结合对细胞周期进程的影响;4)NEDD8与hCul-2的结合在hCul-2-VBC复合体的形成和亚细胞定位中的作用以及在低氧诱导的mRNA调节中的作用,如血管内皮生长因子。
英文摘要
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.
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THE ROLE OF NUB1 IN PATHOGENESIS OF PARKINSON'S DISEASE
THE ROLE OF NUB1 IN PATHOGENESIS OF PARKINSON'S DISEASE
THE ROLE OF NUB1 IN PATHOGENESIS OF PARKINSON'S DISEASE
  • 批准号:
    7672201
  • 项目类别:
  • 资助金额:
    $22.84万
  • 财政年份:
    2006
  • 负责人:
    TETSU KAMITANI
  • 依托单位:
THE ROLE OF NUB1 IN PATHOGENESIS OF PARKINSON'S DISEASE
  • 批准号:
    7626282
  • 项目类别:
  • 资助金额:
    $22.38万
  • 财政年份:
    2006
  • 负责人:
    TETSU KAMITANI
  • 依托单位:
海外基金