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
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs / physiology
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Amino Acid Sequence
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Animals
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Apoptosis / genetics
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Base Sequence
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Down-Regulation / genetics
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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Mice
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Structure, Tertiary / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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RNA Interference
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Protein p14ARF / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / isolation & purification
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Ubiquitin
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HUWE1 protein, human
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Huwe1 protein, mouse
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Ubiquitin-Protein Ligases
Associated data
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GENBANK/AY772009
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GENBANK/AY772010