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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 51; pp. 20681 - 20686
• Main Authors: Le Xuan Truong Nguyen, Mitchell, Beverly S.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 17.12.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Actins; Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Animals; Antibodies; Biological Sciences; Biosynthesis; Casein Kinase II - genetics; Casein Kinase II - metabolism; Cell growth; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cellular immunity; DNA, Ribosomal - genetics; DNA, Ribosomal - metabolism; Enzyme Activation - drug effects; Enzyme Activation - genetics; Gene expression regulation; Humans; K562 Cells; Kinases; Mice; Morpholines - pharmacology; Phosphorylation; Phosphorylation - drug effects; Phosphorylation - genetics; Physiological regulation; 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; Ribonucleic acid; Ribosomal DNA; RNA; RNA polymerase; RNA Polymerase I - genetics; RNA Polymerase I - metabolism; RNA, Ribosomal - biosynthesis; RNA, Ribosomal - genetics; RNA-protein interactions; Transcription, Genetic - physiology; PKB/Akt; acute myelogenous leukemia
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1313097110

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.