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    Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription

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    6
    Author
    Kang, J; Kusnadi, EP; Ogden, AJ; Hicks, RJ; Bammert, L; Kutay, U; Hung, S; Sanij, E; Hannan, RD; Hannan, KM; ...
    Date
    2016-08-02
    Source Title
    Oncotarget
    Publisher
    IMPACT JOURNALS LLC
    University of Melbourne Author/s
    Sanij, Elaine; Hannan, Ross; Pearson, Richard; Hannan, Katherine; Hicks, Rodney; Kusnadi, Eric; Hung, Sandy; Kusnadi, Eric
    Affiliation
    Sir Peter MacCallum Department of Oncology
    Medicine and Radiology
    Biochemistry and Molecular Biology
    Ophthalmology (Eye & Ear Hospital)
    Metadata
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    Document Type
    Journal Article
    Citations
    Kang, J., Kusnadi, E. P., Ogden, A. J., Hicks, R. J., Bammert, L., Kutay, U., Hung, S., Sanij, E., Hannan, R. D., Hannan, K. M. & Pearson, R. B. (2016). Amino acid-dependent signaling via S6K1 and MYC is essential for regulation of rDNA transcription. ONCOTARGET, 7 (31), pp.48887-48904. https://doi.org/10.18632/oncotarget.10346.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259980
    DOI
    10.18632/oncotarget.10346
    NHMRC Grant code
    NHMRC/509087
    NHMRC/566876
    NHMRC/1053792
    NHMRC/566771
    NHMRC/1003270
    NHMRC/1038852
    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.

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