ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.

The INK4a-ARF locus encodes two unrelated proteins that both function in tumor suppression. p16INK4 binds to and inhibits the activity of CDK4 and CDK6, and ARF arrests the cell cycle in a p53-dependent manner. We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2. This ...
interaction is mediated by the exon 1beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The functional consequence of ARF-regulated p53 levels via MDM2 proteolysis is evidenced by the ability of ectopically expressed ARF to restore a p53-imposed G1 cell cycle arrest that is otherwise abrogated by MDM2. Thus, deletion of the ARF-INK4a locus simultaneously impairs both the INK4a-cyclin D/CDK4-RB and the ARF-MDM2-p53 pathways.
Mesh Terms:
Cell Division, Exons, Gene Deletion, Genes, p16, Hela Cells, Humans, Mutagenesis, Nuclear Proteins, Protein Binding, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, Retinoblastoma Protein, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Cell
Date: Mar. 20, 1998
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