title: Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription.
abstract: Dysregulation of RNA polymerase I (Pol I)-dependent ribosomal DNA (rDNA) transcription is a consistent feature of malignant transformation that can be targeted to treat cancer. Understanding how rDNA transcription is coupled to the availability of growth factors and nutrients will provide insight into how ribosome biogenesis is maintained in a tumour environment characterised by limiting nutrients. We demonstrate that modulation of rDNA transcription initiation, elongation and rRNA processing is an immediate, co-regulated response to altered amino acid abundance, dependent on both mTORC1 activation of S6K1 and MYC activity. Growth factors regulate rDNA transcription initiation while amino acids modulate growth factor-dependent rDNA transcription by primarily regulating S6K1-dependent rDNA transcription elongation and processing. Thus, we show for the first time amino acids regulate rRNA synthesis by a distinct, post-initiation mechanism, providing a novel model for integrated control of ribosome biogenesis that has implications for understanding how this process is dysregulated in cancer.
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Kusnadi
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Ogden
authors.affiliation: Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Molecular Imaging and Targeted Therapeutics Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.affiliation: Institute of Biochemistry, Department of Biology, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bammert
authors.affiliation: Institute of Biochemistry, Department of Biology, Swiss Federal Institute of Technology Zurich, Zurich, Switzerland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kutay
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital & Department of Ophthalmology, University of Melbourne, East Melbourne, Victoria, Australia.
authors.forename: Sandy
authors.initials: S
authors.lastname: Hung
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
authors.forename: Elaine
authors.initials: E
authors.lastname: Sanij
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.|School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.|Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberaa, ACT, Australia.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberaa, ACT, Australia.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Hannan
authors.affiliation: Oncogenic Signaling and Growth Control Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D002466:Cell Nucleolus / Q000378:metabolism; D004275:DNA, Ribosomal / Q000737:chemistry / Q000235:genetics*; D005799:Genes, Dominant; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D009857:Oncogenes; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000596:Amino Acids; D004275:DNA, Ribosomal; D036341:Intercellular Signaling Peptides and Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D000076222:Mechanistic Target of Rapamycin Complex 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: Gerotarget; MYC; S6K1; amino acids; rDNA transcription