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The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy.
Biochim Biophys Acta 2015; 1849(7):821-9BB

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.

Authors+Show Affiliations

Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia. Electronic address: rick.pearson@petermac.org.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia; School of Biomedical Sciences, University of Queensland, Queensland 4072, Australia. Electronic address: ross.hannan@petermac.org.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

25464032

Citation

Woods, Simone J., et al. "The Nucleolus as a Fundamental Regulator of the P53 Response and a New Target for Cancer Therapy." Biochimica Et Biophysica Acta, vol. 1849, no. 7, 2015, pp. 821-9.
Woods SJ, Hannan KM, Pearson RB, et al. The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy. Biochim Biophys Acta. 2015;1849(7):821-9.
Woods, S. J., Hannan, K. M., Pearson, R. B., & Hannan, R. D. (2015). The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy. Biochimica Et Biophysica Acta, 1849(7), pp. 821-9. doi:10.1016/j.bbagrm.2014.10.007.
Woods SJ, et al. The Nucleolus as a Fundamental Regulator of the P53 Response and a New Target for Cancer Therapy. Biochim Biophys Acta. 2015;1849(7):821-9. PubMed PMID: 25464032.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy. AU - Woods,Simone J, AU - Hannan,Katherine M, AU - Pearson,Richard B, AU - Hannan,Ross D, Y1 - 2014/11/11/ PY - 2014/09/13/received PY - 2014/10/30/revised PY - 2014/10/31/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2015/8/22/medline KW - Cancer therapy KW - Nucleolar stress KW - Nucleolus KW - RNA polymerase I inhibition KW - p53 SP - 821 EP - 9 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1849 IS - 7 N2 - 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. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/25464032/The_nucleolus_as_a_fundamental_regulator_of_the_p53_response_and_a_new_target_for_cancer_therapy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1874-9399(14)00274-0 DB - PRIME DP - Unbound Medicine ER -