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

Marella Maroder, Antonietta R. Farina, Alessandra Vacca, Maria Pia Felli, Daniela Meco, Isabella Screpanti, L. Frati, A. Gulino

Research output: Contribution to journalArticle

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Abstract

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 chloram-phenicol acetyl-transferase expression. Synergism required an intact GR DMA-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.

Original languageEnglish
Pages (from-to)570-584
Number of pages15
JournalMolecular Endocrinology
Volume7
Issue number4
Publication statusPublished - Apr 1993

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jun Genes
Glucocorticoid Receptors
Tetradecanoylphorbol Acetate
Mouse mammary tumor virus
Terminal Repeat Sequences
T-Lymphocytes
Protein Kinase C
Aptitude
Transcription Factor AP-1
Transferases
HeLa Cells
Dexamethasone
Transcriptional Activation
Transfection
Cellular Microenvironment
Staurosporine
Protein C Inhibitor
Phorbol Esters
Chloramphenicol
Protein Kinase Inhibitors

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism

Cite this

Maroder, M., Farina, A. R., Vacca, A., Felli, M. P., Meco, D., Screpanti, I., ... Gulino, A. (1993). Cell-specific bifunctional role of jun oncogene family members on glucocorticoid receptor-dependent transcription. Molecular Endocrinology, 7(4), 570-584.

Cell-specific bifunctional role of jun oncogene family members on glucocorticoid receptor-dependent transcription. / Maroder, Marella; Farina, Antonietta R.; Vacca, Alessandra; Felli, Maria Pia; Meco, Daniela; Screpanti, Isabella; Frati, L.; Gulino, A.

In: Molecular Endocrinology, Vol. 7, No. 4, 04.1993, p. 570-584.

Research output: Contribution to journalArticle

Maroder, M, Farina, AR, Vacca, A, Felli, MP, Meco, D, Screpanti, I, Frati, L & Gulino, A 1993, 'Cell-specific bifunctional role of jun oncogene family members on glucocorticoid receptor-dependent transcription', Molecular Endocrinology, vol. 7, no. 4, pp. 570-584.
Maroder M, Farina AR, Vacca A, Felli MP, Meco D, Screpanti I et al. Cell-specific bifunctional role of jun oncogene family members on glucocorticoid receptor-dependent transcription. Molecular Endocrinology. 1993 Apr;7(4):570-584.
Maroder, Marella ; Farina, Antonietta R. ; Vacca, Alessandra ; Felli, Maria Pia ; Meco, Daniela ; Screpanti, Isabella ; Frati, L. ; Gulino, A. / Cell-specific bifunctional role of jun oncogene family members on glucocorticoid receptor-dependent transcription. In: Molecular Endocrinology. 1993 ; Vol. 7, No. 4. pp. 570-584.
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