| Abstract: |
Many signals that cause apoptotic cell death operate by inducing transcription and translation of other (presumably death effector) mediators, and it is well established that stimulus-induced apoptosis can often be blocked by inhibiting transcription and translation. Transcriptional regulation of apoptosis, however, is incompletely understood. To gain insight into nuclear events associated with signal-induced apoptosis during T cell development, we studied signal-induced apoptosis of ex vivo isolated immature CD8+4+ double-positive (DP) thymocytes. Stimuli utilizing the T cell receptor (TCR) signaling pathway or its parts (an αCD3/TCR monoclonal antibody, a Ca2+ ionophore, or a protein kinase C-activating phorbol ester) or a stimulus that antagonizes TCR signaling and apoptosis in T cell hybridoma (forskolin, a cyclic AMP-signaling activator) resulted in massive apoptosis of DP thymocytes. At the same time, these stimuli induced qualitatively similar but quantitatively unique patterns of inducible transcription factors (TFs) NF-κB/RelA-p50, AP-1 (Fos-Jun), and NUR-77. We focused our attention on the role of AP-1 (Fos-Jun) complex, which was strongly induced by all of the above stimuli and thus was a candidate for a proapoptotic TF. However, we found that AP-1/c-Fos induction was vital in prolonging DP thymocyte life, as judged by increased spontaneous and induced death of DP cells in Fos(-/-) mice. In direct support of this hypothesis, experiments with antisense oligonucleotides demonstrated that c-Fos plays an essential role in protecting normal DP thymocytes from Ca2+- and cAMP- induced apoptosis but not from TCR-mediated death. Together, these results demonstrate a physiological role for c-Fos in maintaining longevity of DP thymocytes. |
| Keywords: |
signal transduction; dna-binding proteins; nonhuman; cd8 antigen; cd8-positive t-lymphocytes; animal cell; animals; mice; cell death; apoptosis; membrane proteins; transcription factor; immunoglobulin enhancer binding protein; transcription factors; t lymphocyte receptor; transcription regulation; receptors, antigen, t-cell; nf-kappa b; cd4-positive t-lymphocytes; cyclic amp; cd4 antigen; dna binding; receptors, steroid; thymocyte; calcium ionophore; phorbol ester; cyclic amp response element-binding protein; oligonucleotides, antisense; northern blotting; adaptor proteins, vesicular transport; receptors, cytoplasmic and nuclear; transcription factor ap 1; lymphocyte subpopulation; antisense oligonucleotide; protein c fos; proto-oncogene proteins c-fos; protein kinase c activator; female; priority journal; article; oncogene c fos; adaptor protein complex alpha subunits
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