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Submitted on May 19, 2004
Accepted on February 2, 2005
INSERM U 461, Faculté de Pharmacie Paris-XI, 92296 Chatenay-Malabry France.; INSERM U 478, Faculté de Médecine X. Bichat, 75870 Paris France
* To whom correspondence should be addressed. E-mail: marc.pallardy{at}cep.u-psud.fr.
We have analyzed the promoter of human gilz (Glucocorticoid-Induced Leucine Zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC) responsive elements (GREs) and three Forkhead responsive elements (FHREs). Promoter deletion analysis and point mutations showed that individual mutation of the GREs does not affect GC-induced transcription and that FHRE-1 and FHRE-3 elements contribute to the effects of GC. Furthermore, overexpression of the Forkhead transcription factor FoxO3 enhances GC-induced gilz mRNA expression. The functional significance of the interaction between FoxO3 and GR was established in T-lymphocytes. Indeed, we show that GC failed to induce GILZ expression in the presence of interleukin-2 (IL-2) a cytokine known to antagonize GC effects in T-cells. Using a constitutive active mutant of protein kinase B (PKB) that inactivates FoxO3 or a FoxO3 mutant that can not be inactivated by PKB, we demonstrate that IL-2 inhibitory effects on GILZ expression are mediated through inhibition of FoxO3 transcriptional activity. Therefore FoxO3 appears to be a key factor mediating GC and IL-2 antagonism for gilz regulation in T-lymphocytes. This regulation of GILZ expression was placed in a meaningfull context in evaluating the effects of GILZ on GC-induced apoptosis in T-lymphocytes.
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