Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/274

Filters

2003 - 2008 3
3
Reset filters

Settings
Statistics
Citations
Author: Hannan, Ross × Start date: 2003 × End date: 2009 ×

Search Results

Now showing 1 - 3 of 3
  • Item
    No Preview Available
    mTOR-Dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF
    Hannan, KM ; Brandenburger, Y ; Jenkins, A ; Sharkey, K ; Cavanaugh, A ; Rothblum, L ; Moss, T ; Poortinga, G ; McArthur, GA ; Pearson, RB ; Hannan, RD (AMER SOC MICROBIOLOGY, 2003-12)
    Mammalian target of rapamycin (mTOR) is a key regulator of cell growth acting via two independent targets, ribosomal protein S6 kinase 1 (S6K1) and 4EBP1. While each is known to regulate translational efficiency, the mechanism by which they control cell growth remains unclear. In addition to increased initiation of translation, the accelerated synthesis and accumulation of ribosomes are fundamental for efficient cell growth and proliferation. Using the mTOR inhibitor rapamycin, we show that mTOR is required for the rapid and sustained serum-induced activation of 45S ribosomal gene transcription (rDNA transcription), a major rate-limiting step in ribosome biogenesis and cellular growth. Expression of a constitutively active, rapamycin-insensitive mutant of S6K1 stimulated rDNA transcription in the absence of serum and rescued rapamycin repression of rDNA transcription. Moreover, overexpression of a dominant-negative S6K1 mutant repressed transcription in exponentially growing NIH 3T3 cells. Rapamycin treatment led to a rapid dephosphorylation of the carboxy-terminal activation domain of the rDNA transcription factor, UBF, which significantly reduced its ability to associate with the basal rDNA transcription factor SL-1. Rapamycin-mediated repression of rDNA transcription was rescued by purified recombinant phosphorylated UBF and endogenous UBF from exponentially growing NIH 3T3 cells but not by hypophosphorylated UBF from cells treated with rapamycin or dephosphorylated recombinant UBF. Thus, mTOR plays a critical role in the regulation of ribosome biogenesis via a mechanism that requires S6K1 activation and phosphorylation of UBF.
  • Item
    No Preview Available
    Chromatin organization and expression.
    Sanij, E ; Hannan, RD (Springer Science and Business Media LLC, 2008-04-14)
    A report on the 29th Lorne Genome Conference on the Organization and Expression of the Genome, Lorne, Australia, 17-21 February 2008.
  • Item
    Thumbnail Image
    UBF levels determine the number of active ribosomal RNA genes in mammals
    Sanij, E ; Poortinga, G ; Sharkey, K ; Hung, S ; Holloway, TP ; Quin, J ; Robb, E ; Wong, LH ; Thomas, WG ; Stefanovsky, V ; Moss, T ; Rothblum, L ; Hannan, KM ; McArthur, GA ; Pearson, RB ; Hannan, RD (ROCKEFELLER UNIV PRESS, 2008-12-29)
    In mammals, the mechanisms regulating the number of active copies of the approximately 200 ribosomal RNA (rRNA) genes transcribed by RNA polymerase I are unclear. We demonstrate that depletion of the transcription factor upstream binding factor (UBF) leads to the stable and reversible methylation-independent silencing of rRNA genes by promoting histone H1-induced assembly of transcriptionally inactive chromatin. Chromatin remodeling is abrogated by the mutation of an extracellular signal-regulated kinase site within the high mobility group box 1 domain of UBF1, which is required for its ability to bend and loop DNA in vitro. Surprisingly, rRNA gene silencing does not reduce net rRNA synthesis as transcription from remaining active genes is increased. We also show that the active rRNA gene pool is not static but decreases during differentiation, correlating with diminished UBF expression. Thus, UBF1 levels regulate active rRNA gene chromatin during growth and differentiation.