Distinct Glucocorticoid Receptor Transcriptional Regulatory Surfaces Mediate the Cytotoxic and Cytostatic Effects of Glucocorticoids

• DOI: 10.1128/mcb.19.7.5036
• Publication Date: 2015-10-26T10:19:28Z
• Authors: Inez Rogatsky; Adam B. Hittelman; David Pearce; Michael J. Garabe...
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; Cytotoxicity, Immunologic; Transcriptional Activation; 0301 basic medicine; Tumor Suppressor Proteins; Cell Cycle; Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; 3. Good health; Mifepristone; 03 medical and health sciences; Receptors, Glucocorticoid; Proto-Oncogene Proteins c-bcl-2; Mutagenesis; Cyclins; Tumor Cells, Cultured; Humans; Dimerization; Glucocorticoids; Microtubule-Associated Proteins; Cyclin-Dependent Kinase Inhibitor p27

Glucocorticoids act through the glucocorticoid receptor (GR), which can function as a transcriptional activator or repressor, to elicit cytostatic and cytotoxic effects in variety of cells. The molecular mechanisms regulating these events target genes affected by activated remain largely undefined. Using cultured human osteosarcoma cells model for GR antiproliferative effect, we demonstrate that U20S cells, activation leads irreversible growth inhibition, apoptosis, repression Bcl2. This effect is mediated GR’s function, since transactivation-deficient mutants ligands still bring about apoptosis Bcl2 down-regulation. In contrast, SAOS2 reversible, does not result Bcl2, receptor’s ability stimulate transcription. Thus, versus outcome treatment cell context dependent. Interestingly, glucocorticoids involves multiple surfaces. disrupt individual functions (activation 1 [AF-1] AF-2) dimerization fail fully inhibit cellular proliferation and, remarkably, discriminate between targets action, cyclin-dependent kinase inhibitors p21Cip1 p27Kip1. Induction agonist dependent requires AF-2 but AF-1 dimerization. induction p27Kip1 independent, require AF-1, depends on Our findings indicate regulatory employ distinct surfaces are used evoke either response glucocorticoids.