title: Akt/PKB interacts with the histone H3 methyltransferase SETDB1 and coordinates to silence gene expression.
abstract: Serine/threonine kinase Akt (also called protein kinase B, PKB) is a downstream effector of phosphoinositide 3-kinase (PI3K) and functions as the focal point for many signal transduction pathways such as glucose metabolism, transcription, cell survival, angiogenesis, and cell motility. Akt is emerging as a central player in tumorigenesis including human ovarian, pancreatic, prostate, breast, and gastric cancers. However, the function and mechanism by which Akt regulate gene transcription in nucleus remains largely unclear. Here we identify histone methyltransferase SETDB1 as a novel nuclear interacting partner of Akt. By yeast two-hybrid screening, we obtained the Akt1-SETDB1 interaction and confirmed the binding both in vitro and in vivo. Both Akt1 and SETDB1 are co-localized in the nucleus in mammalian cells. SETDB1 is not a phosphorylation substrate of Akt kinase. Akt and SETDB1 could coordinate to regulate the activity of certain transcription factors such as forkhead family member. Due to the fact that SETDB1 acts as a specific histone H3, lysine 9-methyltransferase in vivo, we provide the first link between Akt kinase and histone methyltransferase (HMTase). This interaction represents a novel mechanism by which Akt regulates nuclear events including gene transcription.
authors.affiliation: Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, 250012, PR China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Gao
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.forename: Dongsong
authors.initials: D
authors.lastname: Bi
authors.forename: Liyu
authors.initials: L
authors.lastname: Jiang
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Cui
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Sun
authors.forename: Rong
authors.initials: R
authors.lastname: Ma
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D020868:Gene Silencing / Q000502:physiology*; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology*; D020798:Two-Hybrid System Techniques
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human; D051057:Proto-Oncogene Proteins c-akt