AKT1 has dual actions on the glucocorticoid receptor by cooperating with 14-3-3

Tanwir Habib; Ameera Sadoun; Nancy Nader; Shigeru Suzuki; Wei Liu; Puthen V Jithesh; Tomoshige Kino

doi:10.1016/j.mce.2016.10.002

AKT1 has dual actions on the glucocorticoid receptor by cooperating with 14-3-3

Mol Cell Endocrinol. 2017 Jan 5:439:431-443. doi: 10.1016/j.mce.2016.10.002. Epub 2016 Oct 4.

Authors

Tanwir Habib¹, Ameera Sadoun², Nancy Nader³, Shigeru Suzuki⁴, Wei Liu⁵, Puthen V Jithesh⁶, Tomoshige Kino⁷

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.

PMID: 27717743
DOI: 10.1016/j.mce.2016.10.002

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.

Keywords: Histone modification; Nuclear translocation; Phosphorylation; Protein-protein interaction; Transcriptomics.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural

MeSH terms

14-3-3 Proteins / metabolism*
Biomarkers, Tumor / metabolism*
Cell Nucleus / metabolism
Chromatin / metabolism
E1A-Associated p300 Protein / metabolism
Exoribonucleases / metabolism*
Gene Expression Regulation / drug effects
Glucocorticoids / pharmacology
HCT116 Cells
Histone Code
Humans
Jurkat Cells
Mammary Tumor Virus, Mouse / genetics
Mutant Proteins / metabolism
Phosphorylation / drug effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Promoter Regions, Genetic
Protein Binding / drug effects
Protein Domains
Protein Isoforms / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
Receptors, Glucocorticoid / chemistry
Receptors, Glucocorticoid / metabolism*
Response Elements / genetics
Serine / genetics
Transcription, Genetic / drug effects

Substances

14-3-3 Proteins
Biomarkers, Tumor
Chromatin
Glucocorticoids
Mutant Proteins
Protein Isoforms
Receptors, Glucocorticoid
YWHAH protein, human
Serine
E1A-Associated p300 Protein
EP300 protein, human
AKT1 protein, human
Proto-Oncogene Proteins c-akt
Exoribonucleases
SFN protein, human

Grants and funding

Z01 HD008732/HD/NICHD NIH HHS/United States