Journal article
Regulation of p53 tetramerization and nuclear export by ARC
Proceedings of the National Academy of Sciences - PNAS, Vol.104(52), pp.20826-20831
12/26/2007
DOI: 10.1073/pnas.0710017104
PMCID: PMC2409226
PMID: 18087040
Abstract
Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.
Details
- Title: Subtitle
- Regulation of p53 tetramerization and nuclear export by ARC
- Creators
- Roger S-Y Foo - Albert Einstein College of MedicineYoung-Jae Nam - Albert Einstein College of MedicineMarc Jason Ostreicher - Albert Einstein College of MedicineMark D Metzl - Albert Einstein College of MedicineRussell S Whelan - Yeshiva UniversityChang-Fu Peng - Albert Einstein College of MedicineAnthony W Ashton - Albert Einstein College of MedicineWeimin FuKartik Mani - Yeshiva UniversitySuet-Feung ChinElena Provenzano - University of CambridgeIan Ellis - Nottingham City HospitalNichola Figg - University of CambridgeSarah Pinder - University of CambridgeMartin R Bennett - University of CambridgeCarlos Caldas - University of CambridgeRichard N Kitsis - Albert Einstein College of Medicine
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.104(52), pp.20826-20831
- DOI
- 10.1073/pnas.0710017104
- PMID
- 18087040
- PMCID
- PMC2409226
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- Wellcome Trust HL80607 / NHLBI NIH HHS R01 HL061550 / NHLBI NIH HHS HL60665 / NHLBI NIH HHS HL61550 / NHLBI NIH HHS R01 HL080607 / NHLBI NIH HHS R01 HL060665 / NHLBI NIH HHS
- Language
- English
- Date published
- 12/26/2007
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984695677102771
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