S6 Kinase is essential for MYC-dependent rDNA transcription in Drosophila
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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.author | Mitchell, Naomi | |
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dc.contributor.author | Tchoubrieva, Elissaveta B | |
dc.contributor.author | Chahal, Arjun | |
dc.contributor.author | Woods, Simone | |
dc.contributor.author | Lee, Amanda | |
dc.contributor.author | Lin, Jane | |
dc.contributor.author | Parsons, Linda | |
dc.contributor.author | Jastrzebski, Katarzyna | |
dc.contributor.author | Poortinga, Gretchen | |
dc.contributor.author | Hannan, Katherine | |
dc.contributor.author | Pearson, Richard B | |
dc.contributor.author | Hannan, Ross | |
dc.contributor.author | Quinn, Leonie | |
dc.date.accessioned | 2016-02-24T22:40:55Z | |
dc.identifier.issn | 0898-6568 | |
dc.identifier.uri | http://hdl.handle.net/1885/98497 | |
dc.description.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. | |
dc.publisher | Elsevier | |
dc.source | Cellular Signalling | |
dc.title | S6 Kinase is essential for MYC-dependent rDNA transcription in Drosophila | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 27 | |
dc.date.issued | 2015 | |
local.identifier.absfor | 111201 - Cancer Cell Biology | |
local.identifier.absfor | 111206 - Haematological Tumours | |
local.identifier.absfor | 111207 - Molecular Targets | |
local.identifier.ariespublication | U3488905xPUB5597 | |
local.type.status | Published Version | |
local.contributor.affiliation | Mitchell, Naomi, University of Melbourne | |
local.contributor.affiliation | Tchoubrieva, Elissaveta B, The University of Melbourne | |
local.contributor.affiliation | Chahal, Arjun, The University of Melbourne | |
local.contributor.affiliation | Woods, Simone, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Lee, Amanda, The University of Melbourne | |
local.contributor.affiliation | Lin, Jane, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Parsons, Linda, The University of Melbourne | |
local.contributor.affiliation | Jastrzebski, Katarzyna, Netherlands Cancer Institute, | |
local.contributor.affiliation | Poortinga, Gretchen, Peter MacCalllum Cancer Centre | |
local.contributor.affiliation | Hannan, Katherine, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Pearson, Richard B, Peter MacCallum Cancer Centre | |
local.contributor.affiliation | Hannan, Ross, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Quinn, Leonie, University of Melbourne | |
local.description.embargo | 2037-12-31 | |
local.bibliographicCitation.startpage | 2045 | |
local.bibliographicCitation.lastpage | 2053 | |
local.identifier.doi | 10.1016/j.cellsig.2015.07.018 | |
dc.date.updated | 2016-02-24T10:07:58Z | |
local.identifier.scopusID | 2-s2.0-84939253503 | |
Collections | ANU Research Publications |
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