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.
authors: Division of Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 8006, Australia.
authors: Joanna C
authors: JC
authors: Chan
authors: Katherine M
authors: KM
authors: Hannan
authors: Kim
authors: K
authors: Riddell
authors: Pui Yee
authors: PY
authors: Ng
authors: Abigail
authors: A
authors: Peck
authors: Rachel S
authors: RS
authors: Lee
authors: Sandy
authors: S
authors: Hung
authors: Megan V
authors: MV
authors: Astle
authors: Megan
authors: M
authors: Bywater
authors: Meaghan
authors: M
authors: Wall
authors: Gretchen
authors: G
authors: Poortinga
authors: Katarzyna
authors: K
authors: Jastrzebski
authors: Karen E
authors: KE
authors: Sheppard
authors: Brian A
authors: BA
authors: Hemmings
authors: Michael N
authors: MN
authors: Hall
authors: Ricky W
authors: RW
authors: Johnstone
authors: Grant A
authors: GA
authors: McArthur
authors: Ross D
authors: RD
authors: Hannan
authors: Richard B
authors: RB
authors: Pearson
mesh_terms: D002455:Cell Division; D004275:DNA, Ribosomal / Q000235:genetics; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012318:RNA Polymerase I / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D012270:Ribosomes; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
chemical_list: D004275:DNA, Ribosomal; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D012318:RNA Polymerase I; D012335:RNA, Ribosomal; D058570:TOR Serine-Threonine Kinases