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

Sci Signal. 2011 Aug 30;4(188):ra56. doi: 10.1126/scisignal.2001754.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Division
  • DNA, Ribosomal / genetics
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes
  • Neoplasms / enzymology
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Polymerase I / metabolism
  • RNA, Ribosomal / biosynthesis*
  • Ribosomes*
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transcription, Genetic

Substances

  • DNA, Ribosomal
  • Multiprotein Complexes
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Ribosomal
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • RNA Polymerase I