p14ARF interacts with the SUMO-conjugating enzyme Ubc9 and promotes the sumoylation of its binding partners.
The p14ARF tumour suppressor regulates a series of cell cycle regulatory proteins to promote cell cycle arrest in response to abnormal hyperproliferative growth stimuli. p14ARF alterations are common in human cancers and, when inherited, confer susceptibility to cutaneous melanoma. We now propose that the mechanism of p14ARF action may involve the covalent modification of its binding partners with the small ubiquitin-related protein SUMO-1. In particular, we demonstrate that p14ARF interacts with the SUMO E2 conjugating enzyme, Ubc9 and enhances the sumoylation of its binding partners, hdm2, E2F-1, HIF-1alpha, TBP-1 and p120E4F. Furthermore, p14ARF-induced sumoylation is abrogated by a subset of melanoma-associated p14ARF mutations. These results provide a mechanism for p14ARF action through a common modification of diverse binding partners.
Rizos
Helen
H
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, Australia. helen_rizos@wmi.usyd.edu.au
Woodruff
Sarah
S
Kefford
Richard F
RF
D017504:Adenovirus E4 Proteins / Q000737:chemistry; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002845:Chromatography; D000939:Epitopes / Q000737:chemistry; D019084:Fluorescent Antibody Technique, Indirect; D019942:Genes, p16; D006801:Humans; D008025:Ligases / Q000737:chemistry; D008545:Melanoma / Q000378:metabolism*; D016296:Mutagenesis; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry; D012878:Skin Neoplasms / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000737:chemistry; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D017504:Adenovirus E4 Proteins; D000939:Epitopes; D012097:Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D025803:Tumor Suppressor Protein p14ARF; D025801:Ubiquitin; C411663:transcription factor p120(E4F); D044763:Ubiquitin-Conjugating Enzymes; D008025:Ligases; D000098843:Ubiquitin-Conjugating Enzyme UBC9