Abstract
The bcl-X gene plays a critical role in apoptosis. Six different isoforms generated by tissue-specific promoter usage and alternative splicing were described. Some of them exert opposite effects on cell death. In mammary epithelial cells glucocorticoids induce bcl-X expression and increase the ratio bcl-X(L) (antiapoptotic)/bcl-X(S) (apoptotic) by activating P4 promoter, which contains two hormone response elements. Here we show that, on mouse thymocytes and T lymphocyte derivative S49 cells, glucocorticoids inhibited transcription from P4 and decreased the ratio bcl-X(L)/bcl-X(S) favoring apoptosis. Upon hormonal treatment, glucocorticoid receptor (GR), steroid receptor coactivator-1, and RNA polymerase II were transiently recruited to P4 promoter, whereas STAT5B was also recruited but remained bound. Concomitant with the release of GR, silencing mediator for retinoic acid receptor and thyroid hormone receptor and histone deacetylase 3 were recruited, histone H3 was deacetylated, and RNA polymerase II left the promoter. Inhibition of STAT5 activity reverted glucocorticoid repression to activation of transcription and was accompanied by stable recruitment of GR and RNA polymerase II to P4.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Apoptosis
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COS Cells
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Chlorocebus aethiops
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Chromatin Immunoprecipitation
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Dexamethasone / pharmacology*
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Electrophoretic Mobility Shift Assay
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Gene Expression Regulation / drug effects*
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Histone Acetyltransferases / metabolism
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Histones / metabolism
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Hormone Antagonists / pharmacology
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Lymphocytes / cytology
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Lymphocytes / metabolism*
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Male
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Mice
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Mifepristone / pharmacology
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Nuclear Receptor Coactivator 1
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Plasmids / metabolism
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Promoter Regions, Genetic / genetics*
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RNA Polymerase II / metabolism
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RNA, Messenger / metabolism
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Receptors, Glucocorticoid / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT5 Transcription Factor / metabolism*
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Thymus Gland / cytology
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Thymus Gland / metabolism*
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Transcription Factors / metabolism
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Transcription, Genetic
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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Histones
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Hormone Antagonists
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RNA, Messenger
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Receptors, Glucocorticoid
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STAT5 Transcription Factor
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STAT5B protein, human
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Transcription Factors
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bcl-X Protein
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Mifepristone
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Dexamethasone
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Histone Acetyltransferases
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NCOA1 protein, human
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Ncoa1 protein, mouse
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Nuclear Receptor Coactivator 1
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RNA Polymerase II