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

Research output: Contribution to journalArticle

73 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20826-20831
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number52
DOIs
StatePublished - Dec 26 2007

Keywords

  • Apoptosis
  • Breast cancer

ASJC Scopus subject areas

  • General

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    Foo, R. S. Y., Nam, Y. J., Ostreicher, M. J., Metzl, M. D., Whelan, R. S., Peng, C. F., Ashton, A. W., Fu, W., Mani, K., Chin, S. F., Provenzano, E., Ellis, I., Figg, N., Pinder, S., Bennett, M. R., Caldas, C., & Kitsis, R. N. (2007). Regulation of p53 tetramerization and nuclear export by ARC. Proceedings of the National Academy of Sciences of the United States of America, 104(52), 20826-20831. https://doi.org/10.1073/pnas.0710017104