Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA

Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):20681-6. doi: 10.1073/pnas.1313097110. Epub 2013 Dec 2.

Abstract

Transcription initiation factor I (TIF-IA) plays an essential role in regulating ribosomal RNA (rRNA) synthesis by tethering RNA polymerase I (Pol I) to the rDNA promoter. We have found that activated Akt enhances rRNA synthesis through the phosphorylation of casein kinase IIα (CK2α) on a threonine residue near its N terminus. CK2 in turn phosphorylates TIF-IA, thereby increasing rDNA transcription. Activated Akt also stabilizes TIF-IA, induces its translocation to the nucleolus, and enhances its interaction with Pol I. Treatment with AZD8055, an inhibitor of both Akt and mammalian target of rapamycin phosphorylation, but not with rapamycin, disrupts Akt-mediated TIF-IA stability, translocation, and activity. These data support a model in which activated Akt enhances rRNA synthesis both by preventing TIF-IA degradation and phosphorylating CK2α, which in turn phosphorylates TIF-IA. This model provides an explanation for the ability of activated Akt to promote cell proliferation and, potentially, transformation.

Keywords: PKB/Akt; acute myelogenous leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • DNA, Ribosomal / genetics
  • DNA, Ribosomal / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Humans
  • K562 Cells
  • Mice
  • Morpholines / pharmacology
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Pol1 Transcription Initiation Complex Proteins / genetics
  • Pol1 Transcription Initiation Complex Proteins / metabolism*
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Polymerase I / genetics
  • RNA Polymerase I / metabolism
  • RNA, Ribosomal / biosynthesis*
  • RNA, Ribosomal / genetics
  • Transcription, Genetic / physiology*

Substances

  • DNA, Ribosomal
  • Morpholines
  • Pol1 Transcription Initiation Complex Proteins
  • RNA, Ribosomal
  • RRN3 protein, human
  • Rrn3 protein, mouse
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • CSNK2A1 protein, human
  • Casein Kinase II
  • Proto-Oncogene Proteins c-akt
  • RNA Polymerase I