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.

MULLER IGAZ L, ; REFOJO D, ; COSTAS MA, ; HOLSBOER F, ; ARZT E.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2002 vol. 30 p. 139 - 148

0167-4889

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.