title: S6 Kinase is essential for MYC-dependent rDNA transcription in Drosophila.
abstract: Increased rates of ribosome biogenesis and biomass accumulation are fundamental properties of rapidly growing and dividing malignant cells. The MYC oncoprotein drives growth predominantly via its ability to upregulate the ribosome biogenesis program, in particular stimulating the activity of the RNA Polymerase I (Pol I) machinery to increase ribosomal RNA (rRNA) transcription. Although MYC function is known to be highly dependent on the cellular signalling context, the pathways interacting with MYC to regulate transcription of ribosomal genes (rDNA) in vivo in response to growth factor status, nutrient availability and cellular stress are only beginning to be understood. To determine factors critical to MYC-dependent stimulation of rDNA transcription in vivo, we performed a transient expression screen for known oncogenic signalling pathways in Drosophila. Strikingly, from the broad range of pathways tested, we found that ribosomal protein S6 Kinase (S6K) activity, downstream of the TOR pathway, was the only factor rate-limiting for the rapid induction of rDNA transcription due to transiently increased MYC. Further, we demonstrated that one of the mechanism(s) by which MYC and S6K cooperate is through coordinate activation of the essential Pol I transcription initiation factor TIF-1A (RRN 3). As Pol I targeted therapy is now in phase 1 clinical trials in patients with haematological malignancies, including those driven by MYC, these data suggest that therapies dually targeting Pol I transcription and S6K activity may be effective in treating MYC-driven tumours.
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Melbourne Australia.
authors.forename: Naomi C
authors.initials: NC
authors.lastname: Mitchell
authors.affiliation: Centre for Animal Biotechnology, Faculty of Veterinary Science, The University of Melbourne, Australia.
authors.forename: Elissaveta B
authors.initials: EB
authors.lastname: Tchoubrieva
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Melbourne Australia.
authors.forename: Arjun
authors.initials: A
authors.lastname: Chahal
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne 3002, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: Woods
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Melbourne Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Melbourne, Australia.
authors.forename: Jane I
authors.initials: JI
authors.lastname: Lin
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Melbourne Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Parsons
authors.affiliation: Netherlands Cancer Institute, Division of Molecular Carcinogenesis, Amsterdam, The Netherlands.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Jastrzebski
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne 3002, Australia.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Poortinga
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne 3002, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Australia; Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Australia.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Hannan
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne 3002, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Australia; Department of Biochemistry and Molecular Biology, Monash University, Australia.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
authors.affiliation: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia; Research Division, Peter MacCallum Cancer Centre, Melbourne 3002, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Australia; Department of Biochemistry and Molecular Biology, Monash University, Australia; Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, Australian National University, Australia. Electronic address: ross.hannan@anu.edu.au.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.affiliation: Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Melbourne Australia. Electronic address: l.quinn@unimelb.edu.au.
authors.forename: Leonie M
authors.initials: LM
authors.lastname: Quinn
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000201:enzymology / Q000648:ultrastructure; D054910:Compound Eye, Arthropod / Q000201:enzymology / Q000648:ultrastructure; D004275:DNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D012469:Salivary Glands / Q000201:enzymology / Q000648:ultrastructure; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004275:DNA, Ribosomal; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1; D019893:Ribosomal Protein S6 Kinases
keywords: Cell growth; Drosophila; MYC; Nucleolus; Ribosome biogenesis; S6 Kinase; TIF1A; rDNA transcription