Related Experiment Video

Updated: Mar 14, 2026

Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
11:07

Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding

Published on: September 21, 2011

17.0K

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

Tanwir Habib1, Ameera Sadoun2, Nancy Nader3

  • 1Division of System Biology, Sidra Medical and Research Center, Out Patient Clinic, PO Box 26999, Al Luqta Street, Education City North Campus, Doha, Qatar.

Molecular and Cellular Endocrinology
|October 9, 2016
PubMed

Insights

Targeting AKT1/14-3-3 interactions may overcome glucocorticoid resistance in acute lymphoblastic leukemia (ALL). This approach could enhance glucocorticoid receptor (GR) function, improving ALL treatment outcomes.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Glucocorticoids are crucial for treating acute lymphoblastic leukemia (ALL).
  • AKT1 activation is common in ALL and linked to glucocorticoid resistance.
  • The interaction between AKT1 and the glucocorticoid receptor (GR) is key to understanding resistance mechanisms.

Purpose of the Study:

  • To investigate the impact of AKT1 on GR-mediated gene transcription.
  • To elucidate the role of AKT1 and 14-3-3 protein in regulating GR activity.
  • To identify potential therapeutic strategies for overcoming glucocorticoid resistance in ALL.

Main Methods:

  • Examined AKT1's influence on GR transcriptional activity in vitro.
  • Investigated the cooperative function of AKT1 and 14-3-3 protein.
  • Analyzed AKT1-dependent modifications of GR and associated proteins (p300, histones) at DNA-binding sites.

Main Results:

  • AKT1 exhibits dual actions on GR transcriptional activity: cytoplasmic retention and nuclear modulation.
  • Phosphorylation of GR at Ser-134 by AKT1 leads to 14-3-3 binding and cytoplasmic sequestration.
  • In the nucleus, AKT1 and 14-3-3 facilitate GR activity via p300 phosphorylation and histone modifications, regulating distinct gene sets.

Conclusions:

  • AKT1 differentially regulates glucocorticoid-responsive genes through cytoplasmic and nuclear mechanisms.
  • Targeting the AKT1/14-3-3 interaction involved in cytoplasmic GR retention presents a potential therapeutic strategy.
  • This strategy may be effective in overcoming glucocorticoid resistance in acute lymphoblastic leukemia.
Keywords:
Histone modificationNuclear translocationPhosphorylationProtein-protein interactionTranscriptomics

More Related Videos

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists10:51

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

13.2K
Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.6K

Related Concept Videos

TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors...
10.8K
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
8.0K
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
1.1K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
13.6K
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
8.9K
The Two-State Receptor Model01:29

The Two-State Receptor Model

The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
3.4K