FoxO3 mediates antagonistic effects of glucocorticoids and interleukin-2 on glucocorticoid-induced leucine zipper expression.
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 and three Forkhead responsive elements (FHREs). Promoter deletion analysis and point mutations showed that individual mutation of the GC-responsive elements does not affect GC-induced transcription and that FHRE-1 and FHRE-3 elements contribute to the effects of GCs. Furthermore, overexpression of the Forkhead transcription factor FoxO3 enhances GC-induced gilz mRNA expression. The functional significance of the interaction between FoxO3 and GC receptor was established in T lymphocytes. Indeed, we show that GCs failed to induce GILZ expression in the presence of IL-2, a cytokine known to antagonize GC effects in T cells. Using a constitutive active mutant of protein kinase B that inactivates FoxO3 or a FoxO3 mutant that cannot be inactivated by protein kinase B, 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 meaningful context in evaluating the effects of GILZ on GC-induced apoptosis in T lymphocytes.
Asselin-Labat
Marie-Liesse
ML
Institut National de la Santé et de la Recherche Médicale, Unité 461, Faculté de Pharmacie Paris XI, 5 rue Jean-Baptiste Clément, 92296 Chātenay-Malabry Cedex, France.
Biola-Vidamment
Armelle
A
Kerbrat
Stéphane
S
Lombès
Marc
M
Bertoglio
Jacques
J
Pallardy
Marc
M
D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014176:Protein Biosynthesis; D020218:Response Elements / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D007376:Interleukin-2; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D003907:Dexamethasone