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J. Biol. Chem., Vol. 278, Issue 20, 18022-18029, May 16, 2003

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Glucocorticoids Inhibit Apoptosis during Fibrosarcoma Development by Transcriptionally Activating Bcl-x_L^*

Duncan M. Gascoyne^§, Robert M. Kypta^¶, and Maria d. M. Vivanco

From  The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB and the ^¶ Prostate Cancer Research Group, Department of Cancer Medicine, Division of Medicine, Imperial College, Du Cane Road, London W12 0NN, United Kingdom

Glucocorticoids influence many physiological processes, and in particular apoptosis, often with opposite effects depending on the cell type examined. We found that during fibrosarcoma development there is a strong increase in apoptosis at the tumor stage, which is repressed by dexamethasone to levels observed in normal fibroblasts. The anti-apoptotic Bcl-2 family protein Bcl-x_L is induced by dexamethasone at the transcriptional level at all stages of fibrosarcoma development. The ligand-activated glucocorticoid receptor (GR) activates the Bcl-x promoter in transient transfection experiments, and GR binds to specific Bcl-x promoter sequences in vitro and in vivo. Furthermore, a GR antagonist abolishes this effect, indicating that Bcl-x_L induction is mediated by GR. Importantly, exogenous Bcl-x_L inhibits apoptosis and caspase-3 activity in fibrosarcoma cells to levels found in dexamethasone-treated fibrosarcoma cells. We conclude that Bcl-x_L is a key target mediating the anti-apoptotic effects of glucocorticoids during fibrosarcoma development. These observations provide further understanding of the molecular basis of glucocorticoid regulation of cell death during tumorigenesis.

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