Glucocorticoid Receptor β Stimulates Akt1 Growth Pathway by Attenuation of PTEN

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, GR alpha and GR beta. The growth inhibitory actions of GCs are mediated via GR alpha, a hormone-induced transcription factor. The GR beta isoform, however, lacks helix 12 of the ligand-binding domain and cannot bind GCs. While we have previously shown that GR beta mRNA is responsive to insulin, the role of GR beta in insulin signaling and growth pathways is unknown. In the present study, we show that GR beta suppresses PTEN expression, leading to enhanced insulin-stimulated growth. These characteristics were independent of the inhibitory qualities that have been reported for GR beta on GR alpha. Additionally, we found that GR beta increased phosphorylation of Akt basally, which was further amplified following insulin treatment. In particular, GR beta specifically targets Akt1 in growth pathways. Our results demonstrate that the GR beta/Akt1 axis is a major player in insulin-stimulated growth.