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The ARF protein product of the ink4a/arf locus is induced by a variety of oncogenic signals. ARF facilitates growth arrest through the p53 pathway by hindering the down-regulation of p53 activity mediated by MDM2, through the formation of a protein complex with MDM2. Here we have explored the possibility that human p14(ARF) activity is integrated with growth regulating pathways other than p53, and report our results that p14(ARF) can control the activity of the E2F transcription factor. p14(ARF) regulates E2F activity in different cell-types, including p53(-/-)/mdm(-/-) MEFs, thus excluding that the effects of p14(ARF) are indirectly caused through MDM2 modulation. p14(ARF) down-regulates E2F-dependent transcription, and in cells undergoing E2F-dependent apoptosis prompts cell cycle arrest. p14(ARF) possesses multiple binding domains for E2F-1, one of which resides within the N-terminal region and coincides with the regulation of E2F activity. A mutational analysis of p14(ARF) indicates that the E2F-1 and MDM2 binding domains can be distinguished. These results highlight the potential interplay between p14(ARF) and E2F, and establish p14(ARF) as a pleiotrophic regulator of cell growth that acts by targetting at least two key pathways in the control of proliferation, namely E2F and p53.

Original publication

DOI

10.1038/sj.onc.1205524

Type

Journal article

Journal

Oncogene

Publication Date

20/06/2002

Volume

21

Pages

4220 - 4230

Keywords

Animals, Apoptosis, Binding Sites, Bone Neoplasms, Cell Cycle, Cell Cycle Proteins, Cell Division, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, Fibroblasts, Gene Expression Regulation, Humans, Mice, Models, Biological, Nuclear Proteins, Osteosarcoma, Protein Interaction Mapping, Protein Structure, Tertiary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Signal Transduction, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53