Abstract
Nuclear localization of p53 is essential for its tumor suppressor function. Here, we have identified Parc, a Parkin-like ubiquitin ligase, as a cytoplasmic anchor protein in p53-associated protein complexes. Parc directly interacts and forms a approximately 1 MDa complex with p53 in the cytoplasm of unstressed cells. In the absence of stress, inactivation of Parc induces nuclear localization of endogenous p53 and activates p53-dependent apoptosis. Overexpression of Parc promotes cytoplasmic sequestration of ectopic p53. Furthermore, abnormal cytoplasmic localization of p53 was observed in a number of neuroblastoma cell lines; RNAi-mediated reduction of endogenous Parc significantly sensitizes these neuroblastoma cells in the DNA damage response. These results reveal that Parc is a critical regulator in controlling p53 subcellular localization and subsequent function.
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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Amino Acid Motifs
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Amino Acid Sequence
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Apoptosis
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Cell Nucleus / metabolism
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Cytoplasm / enzymology
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Cytoplasm / metabolism*
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Cytoplasm / physiology
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Etoposide / pharmacology
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Gene Expression Regulation, Neoplastic
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Glutathione Transferase / metabolism
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Humans
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Ligases* / chemistry
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Ligases* / metabolism
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Ligases* / physiology
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Molecular Sequence Data
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / metabolism*
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Neoplasm Proteins / physiology
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Protein Structure, Tertiary
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RNA, Small Interfering / metabolism
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Sequence Homology, Amino Acid
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / chemistry
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitin-Protein Ligases*
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Ubiquitins / metabolism
Substances
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Neoplasm Proteins
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Nucleic Acid Synthesis Inhibitors
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Ubiquitins
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Etoposide
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Ubiquitin-Protein Ligases
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parkin protein
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Glutathione Transferase
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Ligases