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Zap70 Signaling Pathway Mediates Glucocorticoid Receptor-Dependent Transcriptional Activation: Role in the Regulation of Annexin 1 Expression in T Cells¹

Mohammad Ishaq^2,*, Gerald DeGray^*, Kathy Mou^*, Angelica Aguilera^*, Jun Yang, Richard A. Lempicki, Allison Hazen^* and Ven Natarajan^2,*

^* Laboratory of Molecular Cell Biology, and Laboratory of Immunopathogenesis and Bioinformatics, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702

We have recently shown that Zap70 is important in retinoid receptor-dependent transactivation in T lymphocytes. We report that Zap70 signaling is also essential in dexamethasone-inducible glucocorticoid receptor (GR)-mediated transactivation in T lymphocytes. Zap70-negative Jurkat T cells and cells reconstituted with inactive Zap70 exhibited attenuated GR-mediated activation as compared with Zap70 reconstituted and wild-type cells. Lck-lacking Jurkat cells were also found to show markedly reduced GR activation, and reconstitution with Lck restored the activation. Gene array and protein analysis showed that the level of annexin 1 (ANXA1), an anti-inflammatory protein known to be induced and released by the glucocorticoid action, was significantly reduced in Zap70-negative and Zap70-inactive Jurkat cells as compared with wild-type cells. Lck-lacking cells were also found to have markedly reduced ANXA1 levels and reconstitution with Lck restored the ANXA1 expression. RNA interference-induced knockdown of Zap70 or Lck in Jurkat cells and peripheral blood T lymphocytes also resulted in the loss of ANXA1 expression. Transcriptional analysis revealed that dexamethasone-inducible GR-mediated activation of ANXA1 promoter was compromised in both Zap70 knocked down peripheral blood T cells and Zap70 or Lck-deficient/Lck-inactive Jurkat cells, indicating an essential role of these kinases in GR-mediated ANXA1 promoter activation in T lymphocytes. To summarize, our data demonstrate an important role for Zap70 signaling in GR-mediated transactivation in T lymphocytes and also point out a crucial role of this kinase in maintaining normal ANXA1 levels in these cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in whole or in part with federal funds under contract NO1-CO-12400 from the National Cancer Institute, National Institutes of Health. The research was supported by the National Institute of Allergy and Infectious Diseases. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

² Address correspondence and reprint requests to Dr. Mohammad Ishaq, Laboratory of Molecular Cell Biology, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702; E-mail address: mishaq{at}mail.nih.gov or Dr. Ven Natarajan, Laboratory of Molecular Cell Biology, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702; E-mail address: vnatarajan{at}mail.nih.gov

³ Abbreviations used in this paper: ANXA, annexin; GR, glucocorticoid receptor; DEX, dexamethasone; TSA, trichostatin A; RNAi, RNA interference; siRNA, short interfering RNA; GRE, glucocorticoid response element; PBT, peripheral blood T; WT, wild type.