The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy

Simone J Woods, Katherine M Hannan, Richard B Pearson, Ross D Hannan

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76 Citations (Scopus)

Abstract

BACKGROUND: Recent studies have highlighted the fundamental role that key oncogenes such as MYC, RAS and PI3K occupy in driving RNA Polymerase I transcription in the nucleolus. In addition to maintaining essential levels of protein synthesis, hyperactivated ribosome biogenesis and nucleolar function plays a central role in suppressing p53 activation in response to oncogenic stress. Consequently, disruption of ribosome biogenesis by agents such as the small molecule inhibitor of RNA Polymerase I transcription, CX-5461, has shown unexpected, potent, and selective effects in killing tumour cells via disruption of nucleolar function leading to activation of p53, independent of DNA damage. SCOPE OF REVIEW: This review will explore the mechanism of DNA damage-independent activation of p53 via the nucleolar surveillance pathway and how this can be utilised to design novel cancer therapies. MAJOR CONCLUSION AND GENERAL SIGNIFICANCE: Non-genotoxic targeting of nucleolar function may provide a new paradigm for treatment of a broad range of oncogene-driven malignancies with improved therapeutic windows. This article is part of a Special Issue entitled: Translation and Cancer.
Original languageEnglish
Pages (from-to)821 - 829
Number of pages9
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1849
Issue number7
DOIs
Publication statusPublished - 2015

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