AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer

Joanna Chan, Katherine M Hannan, Kim Riddell, Pui Yee Ng, Abigail Peck, Rachel S Lee, Sandy Hung, Megan V Astle, Megan Bywater, Meaghan Wall, Gretchen Poortinga, Katarzyna Jastrzebski, Karen E Sheppard, Brian A Hemmings, Michael N Hall, Ricky W Johnstone, Grant A McArthur, Ross D Hannan, Richard B Pearson

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)1 - 10
Number of pages10
JournalScience Signaling
Volume4
Issue number188 (Art. No: ra56)
DOIs
Publication statusPublished - 2011

Cite this

Chan, Joanna ; Hannan, Katherine M ; Riddell, Kim ; Ng, Pui Yee ; Peck, Abigail ; Lee, Rachel S ; Hung, Sandy ; Astle, Megan V ; Bywater, Megan ; Wall, Meaghan ; Poortinga, Gretchen ; Jastrzebski, Katarzyna ; Sheppard, Karen E ; Hemmings, Brian A ; Hall, Michael N ; Johnstone, Ricky W ; McArthur, Grant A ; Hannan, Ross D ; Pearson, Richard B. / AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer. In: Science Signaling. 2011 ; Vol. 4, No. 188 (Art. No: ra56). pp. 1 - 10.
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title = "AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer",
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.",
author = "Joanna Chan and Hannan, {Katherine M} and Kim Riddell and Ng, {Pui Yee} and Abigail Peck and Lee, {Rachel S} and Sandy Hung and Astle, {Megan V} and Megan Bywater and Meaghan Wall and Gretchen Poortinga and Katarzyna Jastrzebski and Sheppard, {Karen E} and Hemmings, {Brian A} and Hall, {Michael N} and Johnstone, {Ricky W} and McArthur, {Grant A} and Hannan, {Ross D} and Pearson, {Richard B}",
year = "2011",
doi = "10.1126/scisignal.2001754",
language = "English",
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pages = "1 -- 10",
journal = "Science Signaling",
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Chan, J, Hannan, KM, Riddell, K, Ng, PY, Peck, A, Lee, RS, Hung, S, Astle, MV, Bywater, M, Wall, M, Poortinga, G, Jastrzebski, K, Sheppard, KE, Hemmings, BA, Hall, MN, Johnstone, RW, McArthur, GA, Hannan, RD & Pearson, RB 2011, 'AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer' Science Signaling, vol. 4, no. 188 (Art. No: ra56), pp. 1 - 10. https://doi.org/10.1126/scisignal.2001754

AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer. / Chan, Joanna; Hannan, Katherine M; Riddell, Kim; Ng, Pui Yee; Peck, Abigail; Lee, Rachel S; Hung, Sandy; Astle, Megan V; Bywater, Megan; Wall, Meaghan; Poortinga, Gretchen; Jastrzebski, Katarzyna; Sheppard, Karen E; Hemmings, Brian A; Hall, Michael N; Johnstone, Ricky W; McArthur, Grant A; Hannan, Ross D; Pearson, Richard B.

In: Science Signaling, Vol. 4, No. 188 (Art. No: ra56), 2011, p. 1 - 10.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - AKT promotes rRNA synthesis and cooperates with c-MYC to stimulate ribosome biogenesis in cancer

AU - Chan, Joanna

AU - Hannan, Katherine M

AU - Riddell, Kim

AU - Ng, Pui Yee

AU - Peck, Abigail

AU - Lee, Rachel S

AU - Hung, Sandy

AU - Astle, Megan V

AU - Bywater, Megan

AU - Wall, Meaghan

AU - Poortinga, Gretchen

AU - Jastrzebski, Katarzyna

AU - Sheppard, Karen E

AU - Hemmings, Brian A

AU - Hall, Michael N

AU - Johnstone, Ricky W

AU - McArthur, Grant A

AU - Hannan, Ross D

AU - Pearson, Richard B

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21878679

U2 - 10.1126/scisignal.2001754

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