p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the sumoylation of its binding partners

The p14(ARF) tumour suppressor regulates a series of cell cycle regulatory proteins to promote cell cycle arrest in response to abnormal hyperproliferative growth stimuli. p14(ARF) alterations are common in human cancers and, when inherited, confer susceptibility to cutaneous melanoma. We now propose that the mechanism of p14(ARF) action may involve the covalent modification of its binding partners with the small ubiquitin-related protein SUMO-1. In particular, we demonstrate that p14(ARF) interacts with the SUMO E2 conjugating enzyme, Ubc9 and enhances the sumoylation of its binding partners, hdm2, E2F-1, HIF-1 alpha, TBP-1 and p120(E4F). Furthermore, p14(ARF)-induced sumoylation is abrogated by a subset of melanoma-associated p14(ARF) mutations. These results provide a mechanism for p14(ARF) action through a common modification of diverse binding partners.