Functional role of SUMO modification in the retinoflastoma tumour suppressor pathway

SUMO 修饰在视网膜母细胞瘤肿瘤抑制途径中的功能作用

• 批准号: 30964378
• 负责人: Professor Dr. Stefan Müller
• 金额: --
• 依托单位: Institut für Biochemie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/30964378?language=en
• 关键词: Functional; role; SUMO; modification; retinoflastoma

The retinoblastoma tumour suppressor is a major regulator of cell proliferation and differentiation. Central to pRB function is the pocket domain, which serves as the main binding region for cellular interaction partners. In tumours pRB is frequently inactivated by mutations in the pocket domain or by binding of viral oncoproteins to this region. A characteristic feature of these viral oncoproteins and many cellular pRB-binding partners is an LxCxE sequence motif, which interacts with pRB´s pocket domain. Distinct posttranslational modifications, including phosphorylation and acetylation help pRB to select the appropriate interaction partner in a given situation. We could recently identify the ubiquitin-like SUMO protein as a novel post-translational modifier of pRB. SUMO is covalently attached to a distinct residue (K720) of pRB within the B box of the pocket region that binds LxCxE-motif proteins. Notably, inhibitors of pRB function, including the viral oncoproteins E1A and E7 and the cellular E1A-like inhibitor of differentiation EID-1, completely abolish SUMO modification of pRB. Conversely, pRB mutants deficient in binding of LxCxE-motif proteins exhibit an enhanced modification by SUMO. These data identify SUMO modification as a novel post-translational modification of pRB and point to a new aspect in the control of pRB function. The major aim of the proposed project is to elucidate how the ubiquitin-like SUMO system could coordinate the physical and functional interaction of pRB with cellular regulators to control cell growth or differentiation.

视网膜母细胞瘤肿瘤抑制因子是细胞增殖和分化的主要调节因子。Pocket结构域是pRB功能的中心，它是细胞相互作用伙伴的主要结合区域。在肿瘤中，pRB经常通过口袋结构域的突变或病毒癌蛋白与该区域的结合而失活。这些病毒癌蛋白和许多细胞内pRb结合伙伴的一个特征是有一个LxCxE序列基序，它与pRb的S口袋结构域相互作用。不同的翻译后修饰，包括磷酸化和乙酰化，帮助PRB在给定的情况下选择合适的相互作用伙伴。我们最近发现泛素样相扑蛋白是一种新的pRb翻译后修饰蛋白。SUMO共价连接到与LxCxE基序蛋白结合的口袋区域B盒内的不同残基(K720)上。值得注意的是，pRb功能的抑制剂，包括病毒癌蛋白E1a和E7以及细胞内E1a样分化抑制因子EID-1，完全取消了pRb的相扑修饰。相反，缺乏LxCxE基序蛋白结合的pRb突变体表现出增强的相扑修饰。这些数据表明，相扑修饰是一种新的pRb翻译后修饰，为pRb功能调控开辟了新的方向。该项目的主要目的是阐明泛素样相扑系统如何协调pRB与细胞调节因子的物理和功能相互作用，以控制细胞的生长或分化。