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Sci. Signal., 30 August 2011
Vol. 4, Issue 188, p. ra56
[DOI: 10.1126/scisignal.2001754]

RESEARCH ARTICLES

AKT Promotes rRNA Synthesis and Cooperates with c-MYC to Stimulate Ribosome Biogenesis in Cancer

Joanna C. Chan1*, Katherine M. Hannan1*, Kim Riddell1, Pui Yee Ng1, Abigail Peck1, Rachel S. Lee1, Sandy Hung1, Megan V. Astle1, Megan Bywater1, Meaghan Wall1,2,3, Gretchen Poortinga1,2, Katarzyna Jastrzebski1, Karen E. Sheppard1, Brian A. Hemmings4, Michael N. Hall5, Ricky W. Johnstone1, Grant A. McArthur1,2,6, Ross D. Hannan1,6,7{dagger}{ddagger}, and Richard B. Pearson1,6,7,8{dagger}{ddagger}

1 Division of Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 8006, Australia.
2 Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
3 Victorian Cancer Cytogenetics Service, St Vincent’s Hospital, Melbourne, Victoria 8006, Australia.
4 Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.
5 Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
6 Department of Medicine, St Vincent’s Hospital, Melbourne, Victoria 8006, Australia.
7 Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia.
8 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

Abstract: Precise regulation of ribosome biogenesis is fundamental to maintain normal cell growth and proliferation, and accelerated ribosome biogenesis is associated with malignant transformation. Here, we show that the kinase AKT regulates ribosome biogenesis at multiple levels to promote ribosomal RNA (rRNA) synthesis. Transcription elongation by RNA polymerase I, which synthesizes rRNA, required continuous AKT-dependent signaling, an effect independent of AKT’s role in activating the translation-promoting complex mTORC1 (mammalian target of rapamycin complex 1). Sustained inhibition of AKT and mTORC1 cooperated to reduce rRNA synthesis and ribosome biogenesis by additionally limiting RNA polymerase I loading and pre-rRNA processing. In the absence of growth factors, constitutively active AKT increased synthesis of rRNA, ribosome biogenesis, and cell growth. Furthermore, AKT cooperated with the transcription factor c-MYC to synergistically activate rRNA synthesis and ribosome biogenesis, defining a network involving AKT, mTORC1, and c-MYC as a master controller of cell growth. Maximal activation of c-MYC–dependent rRNA synthesis in lymphoma cells required AKT activity. Moreover, inhibition of AKT-dependent rRNA transcription was associated with increased lymphoma cell death by apoptosis. These data indicate that decreased ribosome biogenesis is likely to be a fundamental component of the therapeutic response to AKT inhibitors in cancer.

{ddagger} To whom correspondence should be addressed. E-mail: rick.pearson{at}petermac.org (R.B.P.); ross.hannan{at}petermac.org (R.D.H.)

Citation: J. C. Chan, K. M. Hannan, K. Riddell, P. Y. Ng, A. Peck, R. S. Lee, S. Hung, M. V. Astle, M. Bywater, M. Wall, G. Poortinga, K. Jastrzebski, K. E. Sheppard, B. A. Hemmings, M. N. Hall, R. W. Johnstone, G. A. McArthur, R. D. Hannan, R. B. Pearson, AKT Promotes rRNA Synthesis and Cooperates with c-MYC to Stimulate Ribosome Biogenesis in Cancer. Sci. Signal. 4, ra56 (2011).

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