title: CRE-mediated transcriptional activation is involved in cAMP protection of T-cell receptor-induced apoptosis but not in cAMP potentiation of glucocorticoid-mediated programmed cell death.
abstract: Apoptosis of thymic cells induced by glucocorticoids (GC) and T-cell receptor (TCR) engagement are mutually antagonistic. We demonstrate that cAMP enhances GC and antagonizes TCR (anti-CD3) apoptosis on the same cell (DO-11.10 and 2B4.11 T-cell hybridomas). We analyzed the activity of several transcription factors in this cAMP dual, stimulus-dependent, regulatory action. Anti-CD3 increases kB-activity which is inhibited by CPTcAMP or dexamethasone (DEX), supporting the proapoptotic role of NFkB on TCR-induced apoptosis. Anti-CD3 not only increases kB- but diminishes GC response element (GRE)-activity induced by DEX, suggesting that TCR-mediated blockade of GC-induced apoptosis involves not only the proposed antiapoptotic action of NF-kB on GC, but also the inhibition of GRE-regulated proapoptotic genes. To test the involvement of CRE-driven transcription in the cAMP dual apoptotic regulation, cells were transfected with a CRE decoy DNA oligomer. Blockade of CRE transactivation with decoy targeting of CRE completely blocked the protection of TCR-induced apoptosis by cAMP, while it did not modify the enhancement by cAMP on GC-induced apoptosis. We show that CRE-binding factors have a definite role in T-cell apoptosis: they are involved in cAMP protection of TCR- but not in cAMP potentiation of GC-induced apoptosis.
authors.affiliation: Laboratorio de Fisiologia y Biologia Molecular, Departamento de Biología, Universidad de Buenos Aires, Argentina.
authors.forename: Lionel
authors.initials: L
authors.lastname: Muller Igaz
authors.forename: Damian
authors.initials: D
authors.lastname: Refojo
authors.forename: Monica A
authors.initials: MA
authors.lastname: Costas
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006825:Hybridomas; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D013601:T-Lymphocytes; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D011948:Receptors, Antigen, T-Cell; D000242:Cyclic AMP