CELL-SPECIFIC BIFUNCTIONAL ROLE OF JUN ONCOGENE FAMILY MEMBERS ON GLUCOCORTICOID RECEPTOR-DEPENDENT TRANSCRIPTION

被引:67
作者
MARODER, M
FARINA, AR
VACCA, A
FELLI, MP
MECO, D
SCREPANTI, I
FRATI, L
GULINO, A
机构
[1] UNIV ROMA LA SAPIENZA, DEPT EXPTL MED, 324 VIALE REGINA ELENA, I-00161 ROME, ITALY
[2] UNIV ROMA LA SAPIENZA, NATL CANC INST, IST BIOTECHNOL SECT, I-00161 ROME, ITALY
[3] UNIV LAQUILA, DEPT EXPTL MED, I-67100 LAQUILA, ITALY
关键词
D O I
10.1210/me.7.4.570
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:570 / 584
页数:15
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