Poster Presentation 26th Lorne Cancer Conference 2014

Amino acids increase RNA polymerase I transcription through mTORC1 and MYC signaling pathways (#180)

Jian Kang 1 , Eric Kusnadi 1 , Rodney J Hicks 1 , Katherine M Hannan 1 , Richard B Pearson 1
  1. Division of Research, Peter Maccullum Cancer Centre, East Melbourne, VIC, Australia

Mammalian cells have developed a complex and integrated signalling network to monitor and respond to changes in the levels of growth factors and the availability of nutrients and energy sources in the environment that is fundamental for their survival. In proliferating cells, the major energy consuming process is ribosome biogenesis, which is rate limiting for protein synthesis, cell growth and proliferation. Therefore, it is not surprising that the nutrient/energy sensing network converges to control ribosome synthesis. Here we demonstrate that re-addition of amino acid (AA) in AA-depleted Hela cells rapidly increased ribosomal RNA (rRNA) synthesis, pre-rRNA processing and RNA polymerase I loading. Moreover, these increases correlated with increased abundance of ribosomes, protein content per cell and cell size. We also show that glutamine possesses a stimulatory effect on rRNA synthesis. In studies aimed at determining the molecular mechanism underlying AA control of ribosome biogenesis, we examined the roles of AKT, mTORC1 pathway and MYC transcription factor, the key regulators of ribosome biogenesis and cell growth in response to growth factor signaling (Chan et al., 2011). Our results suggested mTORC1 and MYC but not AKT are required for AA-dependent rRNA synthesis. This study thus provides fundamental insight into AA-dependent cell growth and raises the possibility that a key consequence of the metabolic switch seen in cancer cells is to facilitate the elevated ribosome biogenesis and protein synthesis, reinforcing the rationale for targeting the ribosome to treat human malignancy (Bywater et al., 2013).

  1. Bywater, M. J., Pearson, R. B., McArthur, G. A., and Hannan, R. D. (2013). Dysregulation of the basal RNA polymerase transcription apparatus in cancer. Nature reviews Cancer 13, 299-314.
  2. Chan, J. C., Hannan, K. M., Riddell, K., Ng, P. Y., Peck, A., Lee, R. S., Hung, S., Astle, M. V., Bywater, M., Wall, M., et al. (2011). AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer. Science signaling 4, ra56.