Regulation of p53 tetramerization and nuclear export by ARC

Roger S-Y Foo; Young-Jae Nam; Marc Jason Ostreicher; Mark D Metzl; Russell S Whelan; Chang-Fu Peng; Anthony W Ashton; Weimin Fu; Kartik Mani; Suet-Feung Chin; Elena Provenzano; Ian Ellis; Nichola Figg; Sarah Pinder; Martin R Bennett; Carlos Caldas; Richard N Kitsis

doi:10.1073/pnas.0710017104

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Regulation of p53 tetramerization and nuclear export by ARC

Journal article

Open access

Peer reviewed

Regulation of p53 tetramerization and nuclear export by ARC

Roger S-Y Foo, Young-Jae Nam, Marc Jason Ostreicher, Mark D Metzl, Russell S Whelan, Chang-Fu Peng, Anthony W Ashton, Weimin Fu, Kartik Mani, Suet-Feung Chin, …

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

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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.

Active Transport, Cell Nucleus

Breast Neoplasms - embryology

Caspases - metabolism

Cell Line, Tumor

Cytoskeletal Proteins - metabolism

Cytoskeletal Proteins - physiology

Dimerization

Exportin 1 Protein

Gene Expression Regulation, Neoplastic

Humans

Karyopherins - metabolism

Models, Biological

Mutation

Nerve Tissue Proteins - metabolism

Nerve Tissue Proteins - physiology

Protein Structure, Tertiary

Receptors, Cytoplasmic and Nuclear - metabolism

RNA, Small Interfering - metabolism

Transcription, Genetic

Tumor Suppressor Protein p53 - chemistry

Tumor Suppressor Protein p53 - physiology

Details

Title: Subtitle: Regulation of p53 tetramerization and nuclear export by ARC
Creators: Roger S-Y Foo - Albert Einstein College of Medicine
Young-Jae Nam - Albert Einstein College of Medicine
Marc Jason Ostreicher - Albert Einstein College of Medicine
Mark D Metzl - Albert Einstein College of Medicine
Russell S Whelan - Yeshiva University
Chang-Fu Peng - Albert Einstein College of Medicine
Anthony W Ashton - Albert Einstein College of Medicine
Weimin Fu
Kartik Mani - Yeshiva University
Suet-Feung Chin
Elena Provenzano - University of Cambridge
Ian Ellis - Nottingham City Hospital
Nichola Figg - University of Cambridge
Sarah Pinder - University of Cambridge
Martin R Bennett - University of Cambridge
Carlos Caldas - University of Cambridge
Richard 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
NLM abbreviation: Proc Natl Acad Sci U S A
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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