Abstract
The tumor suppressor ARF induces a p53-dependent and -independent cell cycle arrest. Unlike the nucleoplasmic MDM2 and p53, ARF localizes in the nucleolus. The role of ARF in the nucleolus, the molecular target, and the mechanism of its p53-independent function remains unclear. Here we show that ARF interacts with B23, a multifunctional nucleolar protein involved in ribosome biogenesis, and promotes its polyubiquitination and degradation. Overexpression of B23 induces a cell cycle arrest in normal fibroblasts, whereas in cells lacking p53 it promotes S phase entry. Conversely, knocking down B23 inhibits the processing of preribosomal RNA and induces cell death. Further, oncogenic Ras induces B23 only in ARF null cells, but not in cells that retain wild-type ARF. Together, our results reveal a molecular mechanism of ARF in regulating ribosome biogenesis and cell proliferation via inhibiting B23, and suggest a nucleolar role of ARF in surveillance of oncogenic insults.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Division / physiology*
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Cell Line, Tumor
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Cell Nucleolus / chemistry
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Cell Nucleolus / metabolism
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Cell Survival
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Cysteine Endopeptidases / metabolism
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Endoribonucleases / metabolism*
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Gene Expression Regulation
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Humans
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Multienzyme Complexes / metabolism
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Nuclear Proteins / metabolism*
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Nucleophosmin
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Proteasome Endopeptidase Complex
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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RNA, Ribosomal / metabolism
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Ribosomes / genetics
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Ribosomes / metabolism*
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Tumor Suppressor Protein p14ARF / metabolism*
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitin / metabolism
Substances
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Multienzyme Complexes
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Ribosomal
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Ubiquitin
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Nucleophosmin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Endoribonucleases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex