Transcription factor activation during signal-induced apoptosis of immature CD4+CD8+ thymocytes: A protective role of c-Fos

Vladimir N. Ivanov, Janko Nikolich-Zugich

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8558-8566
Number of pages9
JournalJournal of Biological Chemistry
Volume272
Issue number13
StatePublished - Mar 28 1997
Externally publishedYes

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Thymocytes
Transcriptional Activation
Transcription Factors
Chemical activation
Apoptosis
T-Cell Antigen Receptor
Transcription Factor AP-1
T-cells
Transcription
T-Lymphocytes
Antisense Oligonucleotides
Ionophores
Hybridomas
Phorbol Esters
Colforsin
Cell death
Cyclic AMP
Protein Kinase C
Cell Death
Monoclonal Antibodies

ASJC Scopus subject areas

  • Biochemistry

Cite this

Transcription factor activation during signal-induced apoptosis of immature CD4+CD8+ thymocytes : A protective role of c-Fos. / Ivanov, Vladimir N.; Nikolich-Zugich, Janko.

In: Journal of Biological Chemistry, Vol. 272, No. 13, 28.03.1997, p. 8558-8566.

Research output: Contribution to journalArticle

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