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Cell. 1998 Mar 20;92(6):725-34.

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

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  • 1Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, 27599-3280, USA.

Abstract

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.

PMID:
9529249
[PubMed - indexed for MEDLINE]
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