Functional role of SUMO modification in the retinoflastoma tumour suppressor pathway

• Applicant: Professor Dr. Stefan Müller
• Subject Area: Cell Biology
• Term: from 2006 to 2010
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 30964378

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.

• DFG Programme: Research Grants