title: Glucocorticoid receptor β stimulates Akt1 growth pathway by attenuation of PTEN.
abstract: Glucocorticoids (GCs) are known inhibitors of proliferation and are commonly prescribed to cancer patients to inhibit tumor growth and induce apoptosis via the glucocorticoid receptor (GR). Because of alternative splicing, the GR exists as two isoforms, GRα and GRβ. The growth inhibitory actions of GCs are mediated via GRα, a hormone-induced transcription factor. The GRβ isoform, however, lacks helix 12 of the ligand-binding domain and cannot bind GCs. While we have previously shown that GRβ mRNA is responsive to insulin, the role of GRβ in insulin signaling and growth pathways is unknown. In the present study, we show that GRβ suppresses PTEN expression, leading to enhanced insulin-stimulated growth. These characteristics were independent of the inhibitory qualities that have been reported for GRβ on GRα. Additionally, we found that GRβ increased phosphorylation of Akt basally, which was further amplified following insulin treatment. In particular, GRβ specifically targets Akt1 in growth pathways. Our results demonstrate that the GRβ/Akt1 axis is a major player in insulin-stimulated growth.
authors.affiliation: From the Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology and.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Stechschulte
authors.affiliation: the Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, Toledo, Ohio 43614.
authors.forename: Leah
authors.initials: L
authors.lastname: Wuescher
authors.affiliation: the Department of Kinesiology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Marino
authors.affiliation: From the Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology and.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Hill
authors.affiliation: the Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, and the Department of Genetics and Genome Sciences and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.affiliation: From the Center for Hypertension and Personalized Medicine, Department of Physiology and Pharmacology and Terry.Hinds@utoledo.edu.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Hinds
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid; C121943:glucocorticoid receptor beta; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse
keywords: Akt; Cell Growth; Cell Proliferation; Glucocorticoid; Glucocorticoid Receptor; Hormone Receptor; Insulin; Phosphatase and Tensin Homolog (PTEN)