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AKT is a critical regulator of rRNA synthesis and cooperates with c-MYC to control ribosome biogenesis in cancer

Chan, J. C. and Hannan, K. M. and Riddell, K. and Ng, P. Y. and Peck, A. and Lee, R. S. and Hung, S. and Astle, M. V. and Bywater, M. and Wall, M. and Poortinga, G. and Jastrzbeski, K. and Sheppard, K. E. and Hemmings, B. A. and Hall, M. N. and Johnstone, R. W. and McArthur, G. A. and Hannan, R. D. and Pearson, R. B.. (2011) AKT is a critical regulator of rRNA synthesis and cooperates with c-MYC to control ribosome biogenesis in cancer. Science Signaling, 4 (188). ra56.

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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\u2019s 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\u2013dependent rRNA synthesis in lymphoma cells required AKT activity. Moreover, inhibition of AKTdependent 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Association for the Advancement of Science
ISSN:1945-0877
e-ISSN:1937-9145
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:04 Oct 2017 08:21
Deposited On:14 Sep 2012 06:40

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