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S6 Kinase is essential for MYC-dependent rDNA transcription in Drosophila

Mitchell, Naomi; Tchoubrieva, Elissaveta B; Chahal, Arjun; Woods, Simone; Lee, Amanda; Lin, Jane; Parsons, Linda; Jastrzebski, Katarzyna; Poortinga, Gretchen; Hannan, Katherine; Pearson, Richard B; Hannan, Ross; Quinn, Leonie

Description

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...[Show more]

dc.contributor.authorMitchell, Naomi
dc.contributor.authorTchoubrieva, Elissaveta B
dc.contributor.authorChahal, Arjun
dc.contributor.authorWoods, Simone
dc.contributor.authorLee, Amanda
dc.contributor.authorLin, Jane
dc.contributor.authorParsons, Linda
dc.contributor.authorJastrzebski, Katarzyna
dc.contributor.authorPoortinga, Gretchen
dc.contributor.authorHannan, Katherine
dc.contributor.authorPearson, Richard B
dc.contributor.authorHannan, Ross
dc.contributor.authorQuinn, Leonie
dc.date.accessioned2016-02-24T22:40:55Z
dc.identifier.issn0898-6568
dc.identifier.urihttp://hdl.handle.net/1885/98497
dc.description.abstractIncreased 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.
dc.publisherElsevier
dc.sourceCellular Signalling
dc.titleS6 Kinase is essential for MYC-dependent rDNA transcription in Drosophila
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume27
dc.date.issued2015
local.identifier.absfor111201 - Cancer Cell Biology
local.identifier.absfor111206 - Haematological Tumours
local.identifier.absfor111207 - Molecular Targets
local.identifier.ariespublicationU3488905xPUB5597
local.type.statusPublished Version
local.contributor.affiliationMitchell, Naomi, University of Melbourne
local.contributor.affiliationTchoubrieva, Elissaveta B, The University of Melbourne
local.contributor.affiliationChahal, Arjun, The University of Melbourne
local.contributor.affiliationWoods, Simone, Peter MacCallum Cancer Centre
local.contributor.affiliationLee, Amanda, The University of Melbourne
local.contributor.affiliationLin, Jane, Peter MacCallum Cancer Centre
local.contributor.affiliationParsons, Linda, The University of Melbourne
local.contributor.affiliationJastrzebski, Katarzyna, Netherlands Cancer Institute,
local.contributor.affiliationPoortinga, Gretchen, Peter MacCalllum Cancer Centre
local.contributor.affiliationHannan, Katherine, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationPearson, Richard B, Peter MacCallum Cancer Centre
local.contributor.affiliationHannan, Ross, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationQuinn, Leonie, University of Melbourne
local.description.embargo2037-12-31
local.bibliographicCitation.startpage2045
local.bibliographicCitation.lastpage2053
local.identifier.doi10.1016/j.cellsig.2015.07.018
dc.date.updated2016-02-24T10:07:58Z
local.identifier.scopusID2-s2.0-84939253503
CollectionsANU Research Publications

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