title: AKT1 has dual actions on the glucocorticoid receptor by cooperating with 14-3-3.
abstract: Glucocorticoids are important therapeutic compounds for acute lymphoblastic leukemia (ALL). AKT1 or the protein kinase B is frequently activated in ALL, and contributes to the development of glucocorticoid resistance. We examined impact of AKT1 on glucocorticoid receptor (GR)-induced transcriptional activity in cooperation with phospho-serine/threonine-binding protein 14-3-3. AKT1 has two distinct actions on GR transcriptional activity, one through segregation of GR in the cytoplasm by phosphorylating GR at Ser-134 and subsequent association of 14-3-3, and the other through direct modulation of GR transcriptional activity in the nucleus. For the latter, AKT1 and 14-3-3 are attracted to DNA-bound GR, accompanied by AKT1-dependent p300 phosphorylation, H3S10 phosphorylation and H3K14 acetylation at the DNA site. These two actions of AKT1 regulate distinct sets of glucocorticoid-responsive genes. Our results suggest that specific inhibition of the AKT1/14-3-3 activity on the cytoplasmic retention of GR may be a promising target for treating glucocorticoid resistance observed in ALL.
authors.affiliation: Division of System Biology, Sidra Medical and Research Center, Out Patient Clinic, PO Box 26999, Al Luqta Street, Education City North Campus, Doha, Qatar. Electronic address: thabib@sidra.org.
authors.forename: Tanwir
authors.initials: T
authors.lastname: Habib
authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Out Patient Clinic, PO Box 26999, Al Luqta Street, Education City North Campus, Doha, Qatar. Electronic address: asadoun@sidra.org.
authors.forename: Ameera
authors.initials: A
authors.lastname: Sadoun
authors.affiliation: Physiology and Biophysics, Weill Cornell University in Qatar, PO Box 24144, Al Luqta Street, Education City South Campus, Doha, Qatar. Electronic address: nan2017@qatar-med.cornell.edu.
authors.forename: Nancy
authors.initials: N
authors.lastname: Nader
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 10, CRC, Rm 1-3140, 10 Center Drive MSC 1109, Bethesda, MD 20892, USA; Department of Pediatrics, Asahikawa Medical University, Asahikawa, 078-8510, Japan. Electronic address: shige5p@asahikawa-med.ac.jp.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Division of Genomic Core, Sidra Medical and Research Center, Out Patient Clinic, PO Box 26999, Al Luqta Street, Education City North Campus, Doha, Qatar. Electronic address: wliu@sidra.org.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Division of System Biology, Sidra Medical and Research Center, Out Patient Clinic, PO Box 26999, Al Luqta Street, Education City North Campus, Doha, Qatar. Electronic address: PJithesh@sidra.org.
authors.forename: Puthen V
authors.initials: PV
authors.lastname: Jithesh
authors.affiliation: Division of Translational Medicine, Sidra Medical and Research Center, Out Patient Clinic, PO Box 26999, Al Luqta Street, Education City North Campus, Doha, Qatar; Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bldg. 10, CRC, Rm 1-3140, 10 Center Drive MSC 1109, Bethesda, MD 20892, USA. Electronic address: tkino@sidra.org.
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005095:Exoribonucleases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D045325:HCT116 Cells; D042421:Histone Code; D006801:Humans; D019169:Jurkat Cells; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D012694:Serine / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D002843:Chromatin; D005938:Glucocorticoids; D050505:Mutant Proteins; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; C482984:YWHAH protein, human; D012694:Serine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D005095:Exoribonucleases; C413442:SFN protein, human
keywords: Histone modification; Nuclear translocation; Phosphorylation; Protein-protein interaction; Transcriptomics