Transcription factor activation during signal-induced apoptosis of immature CD4(+)CD8(+) thymocytes. A protective role of c-Fos.
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 alphaCD3/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-kappaB/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.
Ivanov
V N
VN
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Nikolić-Zugić
J
J
D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016376:Oligonucleotides, Antisense; D016760:Proto-Oncogene Proteins c-fos; D011948:Receptors, Antigen, T-Cell; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors