ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor

Cell. 2005 Jul 1;121(7):1071-83. doi: 10.1016/j.cell.2005.03.037.

Abstract

Although the importance of the ARF tumor suppressor in p53 regulation is well established, numerous studies indicate that ARF also suppresses cell growth in a p53/Mdm2-independent manner. To understand the mechanism of ARF-mediated tumor suppression, we identified a ubiquitin ligase, ARF-BP1, as a key factor associated with ARF in vivo. ARF-BP1 harbors a signature HECT motif, and its ubiquitin ligase activity is inhibited by ARF. Notably, inactivation of ARF-BP1, but not Mdm2, suppresses the growth of p53 null cells in a manner reminiscent of ARF induction. Surprisingly, in p53 wild-type cells, ARF-BP1 directly binds and ubiquitinates p53, and inactivation of endogenous ARF-BP1 is crucial for ARF-mediated p53 stabilization. Thus, our study modifies the current view of ARF-mediated p53 activation and reveals that ARF-BP1 is a critical mediator of both the p53-independent and p53-dependent tumor suppressor functions of ARF. As such, ARF-BP1 may serve as a potential target for therapeutic intervention in tumors regardless of p53 status.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs / physiology
  • Amino Acid Sequence
  • Animals
  • Apoptosis / genetics
  • Base Sequence
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Down-Regulation / genetics
  • Gene Expression Regulation, Neoplastic / physiology*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary / physiology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2
  • RNA Interference
  • Tumor Suppressor Protein p14ARF / genetics
  • Tumor Suppressor Protein p14ARF / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / isolation & purification
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Ubiquitin
  • HUWE1 protein, human
  • Huwe1 protein, mouse
  • MDM2 protein, human
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • Ubiquitin-Protein Ligases

Associated data

  • GENBANK/AY772009
  • GENBANK/AY772010