title: The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy.
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.
  
  
  METHODS
  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.
  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.affiliation: Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Simone J
authors.initials: SJ
authors.lastname: Woods
authors.affiliation: 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.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Hannan
authors.affiliation: 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.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.affiliation: 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.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage; D006801:Humans; D009287:Naphthyridines / Q000494:pharmacology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D052160:Benzothiazoles; C557717:CX 5461; C489427:MYC protein, human; D009287:Naphthyridines; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D012318:RNA Polymerase I; D018631:ras Proteins
keywords: Cancer therapy; Nucleolar stress; Nucleolus; RNA polymerase I inhibition; p53