ARF Promotes MDM2 Degradation and Stabilizes p53: ARF-INK4a Locus Deletion Impairs Both the Rb and p53 Tumor Suppression Pathways

Cell. 1998 Mar 20;92(6):725-34. doi: 10.1016/s0092-8674(00)81401-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Division / genetics
  • Exons / physiology
  • Gene Deletion
  • Genes, p16 / genetics*
  • HeLa Cells
  • Humans
  • Mutagenesis / physiology
  • Nuclear Proteins*
  • Protein Binding / physiology
  • Proteins / analysis
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / analysis
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2
  • Retinoblastoma Protein / metabolism*
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53 / analysis
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Nuclear Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2