Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes

I. Wu, S. C. Shin, Y. Cao, I. K. Bender, N. Jafari, G. Feng, S. Lin, J. A. Cidlowski, R. P. Schleimer, N. Z. Lu*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Induction of T-cell apoptosis contributes to the anti-inflammatory and antineoplastic benefits of glucocorticoids. The glucocorticoid receptor (GR) translational isoforms have distinct proapoptotic activities in osteosarcoma cells. Here we determined whether GR isoforms selectively induce apoptosis in Jurkat T lymphoblastic leukemia cells. Jurkat cells stably expressing individual GR isoforms were generated and treated with vehicle or dexamethasone (DEX). DEX induced apoptosis in cells expressing the GR-A, -B, or -C, but not the GR-D, isoform. cDNA microarray analyses of cells sensitive (GR-C3) and insensitive (GR-D3) to DEX revealed glucocorticoid-induced proapoptotic transcriptomes. Genes that were regulated by the proapoptotic GR-C3, but not by the GR-D3, isoform likely contributed to glucocorticoid-induced apoptosis. The identified genes include those that are directly involved in apoptosis and those that facilitate cell killing. Chromatin immunoprecipitation assays demonstrated that distinct chromatin modification abilities may underlie the distinct functions of GR isoforms. Interestingly, all GR isoforms, including the GR-D3 isoform, suppressed mitogen-stimulated cytokines. Furthermore, the GR-C isoforms were selectively upregulated in mitogen-activated primary T cells and DEX treatment induced GR-C target genes in activated T cells. Cell-specific expressions and functions of GR isoforms may help to explain the tissue- and individual-selective actions of glucocorticoids and may provide a basis for developing improved glucocorticoids.

Original languageEnglish (US)
Pages (from-to)e453
JournalCell Death and Disease
Volume4
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • T cell
  • alternative translation
  • apoptosis
  • glucocorticoid
  • glucocorticoid receptor

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Wu, I., Shin, S. C., Cao, Y., Bender, I. K., Jafari, N., Feng, G., Lin, S., Cidlowski, J. A., Schleimer, R. P., & Lu, N. Z. (2013). Selective glucocorticoid receptor translational isoforms reveal glucocorticoid-induced apoptotic transcriptomes. Cell Death and Disease, 4(1), e453. https://doi.org/10.1038/cddis.2012.193