Functional role of SUMO modification in the retinoflastoma tumour suppressor pathway

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。pRB功能的中心是口袋结构域，其充当细胞相互作用伴侣的主要结合区域。在肿瘤中，pRB经常由于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pRB结合伴侣的特征是LxCxE序列基序，其与pRB的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适当的相互作用伙伴。我们最近可以确定泛素样SUMO蛋白作为一种新的翻译后修饰的pRB。SUMO共价连接到pRB的不同残基（K720），该残基位于结合LxCxE基序蛋白的口袋区域的B盒内。值得注意的是，pRB功能的抑制剂，包括病毒癌蛋白E1 A和E7以及细胞E1 A样分化抑制剂EID-1，完全消除了pRB的SUMO修饰。相反，pRB突变体的LxCxE基序蛋白结合缺陷表现出增强的修饰SUMO。这些数据确定SUMO修饰作为一种新的pRB的翻译后修饰，并指出一个新的方面在控制pRB功能。该项目的主要目的是阐明泛素样SUMO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。

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.