Molecular Endocrinology, Vol 7, 570-584, Copyright © 1993 by Endocrine Society

ARTICLES

Cell-specific bifunctional role of Jun oncogene family members on glucocorticoid receptor-dependent transcription

M Maroder, AR Farina, A Vacca, MP Felli, D Meco, I Screpanti, L Frati and A Gulino
Department of Experimental Medicine, University La Sapienza, Rome, Italy.

Interaction between protein kinase C (PKC)- and glucocorticoid receptor (GR)-mediated signaling is suggested by the ability of the PKC activating phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to inhibit GR-dependent transcription of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). Here we report that this interference is cell specific, as TPA augmented dexamethasone-induced transcriptional activation of the MMTV LTR in several T cell lines but was inhibitory in NIH-3T3 fibroblasts. TPA-GR synergism was determined to have occurred at the GR-responsive element (GRE) level by functional analysis of deletion mutants or synthetic GRE oligonucleotides driving chloramphenicol acetyl-transferase expression. Synergism required an intact GR DNA-binding domain, whereas amino- or carboxyl-terminal domains were dispensable. The effect was abrogated by the PKC inhibitor staurosporine, suggesting a role for PKC. Increased c-jun, jun-B, and jun-D expression above basal levels and increased transcriptional activity of AP-1/TPA responsive elements fused to chloramphenicol acetyl-transferase vectors were observed in T cells treated with TPA alone or in combination with dexamethasone. The ability of Jun proteins to cooperate with GR in T cells has been investigated after transfection of c-jun, jun-B, or jun-D expression vectors, which augmented GR-dependent transcription from either MMTV LTR or GRE. Conversely, c-jun and jun-B transfection blunted GR-dependent transcription in HeLa cells. The presence of c-fos had a negative influence on GR function and correlated with the cell-specific synergistic or antagonistic activity of Jun with respect to GR; high basal expression of c-fos as well as AP-1 DNA binding and transcriptional activity were observed in HeLa cells, but not in T cells. Furthermore overexpression of exogenous c-fos has an inhibitory effect on GR-dependent transcription from GRE in T cells. We propose that Jun plays a bifunctional role on GR-dependent transcriptional activation of GRE, selecting either synergistic or antagonistic activity depending on the cell-specific microenvironment. In this regard, intracellular levels of c-fos appear to be influential.

This article has been cited by other articles:

				H. Kimura, X. Li, K. Torii, T. Okada, K. Kamiyama, D. Mikami, N. Takahashi, and H. Yoshida Dexamethasone enhances basal and TNF-{alpha}-stimulated production of PAI-1 via the glucocorticoid receptor regardless of 11{beta}-hydroxysteroid dehydrogenase 2 status in human proximal renal tubular cells Nephrol. Dial. Transplant., June 1, 2009; 24(6): 1759 - 1765. [Abstract] [Full Text] [PDF]

				A Cote-Velez, L Perez-Martinez, M Y Diaz-Gallardo, C Perez-Monter, A Carreon-Rodriguez, J-L Charli, and P Joseph-Bravo Dexamethasone represses cAMP rapid upregulation of TRH gene transcription: identification of a composite glucocorticoid response element and a cAMP response element in TRH promoter J. Mol. Endocrinol., February 1, 2005; 34(1): 177 - 197. [Abstract] [Full Text] [PDF]

				A. Chen, J. Vaughan, and W. W. Vale Glucocorticoids Regulate the Expression of the Mouse Urocortin II Gene: A Putative Connection between the Corticotropin-Releasing Factor Receptor Pathways Mol. Endocrinol., August 1, 2003; 17(8): 1622 - 1639. [Abstract] [Full Text] [PDF]

				P. J. Smith, D. J. Cousins, Y.-K. Jee, D. Z. Staynov, T. H. Lee, and P. Lavender Suppression of Granulocyte-Macrophage Colony-Stimulating Factor Expression by Glucocorticoids Involves Inhibition of Enhancer Function by the Glucocorticoid Receptor Binding to Composite NF-AT/Activator Protein-1 Elements J. Immunol., September 1, 2001; 167(5): 2502 - 2510. [Abstract] [Full Text] [PDF]

				C. D. Meiering, C. Rubio, C. May, and M. L. Linial Cell-Type-Specific Regulation of the Two Foamy Virus Promoters J. Virol., July 15, 2001; 75(14): 6547 - 6557. [Abstract] [Full Text]

				A. Biola, P. Lefebvre, M. Perrin-Wolff, M. Sturm, J. Bertoglio, and M. Pallardy Interleukin-2 Inhibits Glucocorticoid Receptor Transcriptional Activity through a Mechanism Involving STAT5 (Signal Transducer and Activator of Transcription 5) but Not AP-1 Mol. Endocrinol., July 1, 2001; 15(7): 1062 - 1076. [Abstract] [Full Text] [PDF]

				X.-F. Zhou, X.-Q. Shen, and L. Shemshedini Ligand-Activated Retinoic Acid Receptor Inhibits AP-1 Transactivation by Disrupting c-Jun/c-Fos Dimerization Mol. Endocrinol., February 1, 1999; 13(2): 276 - 285. [Abstract] [Full Text]

				I. Borcsok, H. U. Schairer, U. Sommer, G. K. Wakley, U. Schneider, F. Geiger, F. U. Niethard, R. Ziegler, and C. H. Kasperk Glucocorticoids Regulate the Expression of the Human Osteoblastic Endothelin A Receptor Gene J. Exp. Med., November 2, 1998; 188(9): 1563 - 1573. [Abstract] [Full Text] [PDF]

				A. Philips, C. Teyssier, F. Galtier, C. Rivier-Covas, J.-M. Rey, H. Rochefort, and D. Chalbos FRA-1 Expression Level Modulates Regulation of Activator Protein-1 Activity by Estradiol in Breast Cancer Cells Mol. Endocrinol., July 1, 1998; 12(7): 973 - 985. [Abstract] [Full Text]

				A. Bubulya, S. C. Wise, X.-Q. Shen, L. A. Burmeister, and L. Shemshedini c-Jun Can Mediate Androgen Receptor-induced Transactivation J. Biol. Chem., October 4, 1996; 271(40): 24583 - 24589. [Abstract] [Full Text] [PDF]

				H. Oshima, D. Szapary, and S. S. Simons Jr. The Factor Binding to the Glucocorticoid Modulatory Element of the Tyrosine Aminotransferase Gene Is a Novel and Ubiquitous Heteromeric Complex J. Biol. Chem., September 15, 1995; 270(37): 21893 - 21901. [Abstract] [Full Text] [PDF]

				M. Cippitelli, A. Sica, V. Viggiano, J. Ye, P. Ghosh, M. J. Birrer, and H. A. Young Negative Transcriptional Regulation of the Interferon-[IMAGE] Promoter by Glucocorticoids and Dominant Negative Mutants of c-Jun J. Biol. Chem., May 26, 1995; 270(21): 12548 - 12556. [Abstract] [Full Text] [PDF]

				S.-c. Hsu and D. B. DeFranco Selectivity of Cell Cycle Regulation of Glucocorticoid Receptor Function J. Biol. Chem., February 17, 1995; 270(7): 3359 - 3364. [Abstract] [Full Text] [PDF]