title: Akt activation enhances ribosomal RNA synthesis through casein kinase II and TIF-IA.
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.
authors.affiliation: Department of Medicine and Department of Chemical and Systems Biology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Le Xuan Truong
authors.initials: le XT
authors.lastname: Nguyen
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Mitchell
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020014:K562 Cells; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012318:RNA Polymerase I / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D004275:DNA, Ribosomal; D009025:Morpholines; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C428423:RRN3 protein, human; C491074:Rrn3 protein, mouse; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D012318:RNA Polymerase I
keywords: PKB/Akt; acute myelogenous leukemia