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

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

Author information

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.

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

PMID:
27717743
DOI:
10.1016/j.mce.2016.10.002
[Indexed for MEDLINE]

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