DNA damage-induced apoptosis and Ice gene induction in mitogenically activated T lymphocytes require IRF-1.
Lymphocytes are highly sensitive to DNA damage-induced apoptosis. In thymocytes, the tumor suppressor p53 has been shown to be required for this type of apoptosis. However an as yet unknown, p53-independent pathway(s) appears to mediate the same event in mitogenically activated mature T lymphocytes. By using mice with a null mutation in the IRF-1 gene, we revealed that DNA damage-induced apoptosis in the latter cell type is dependent on the anti-oncogenic transcription factor interferon regulatory factor-1 (IRF-1). Thus two different anti-oncogenic transcription factors, p53 and IRF-1, are required for distinct apoptotic pathways in T lymphocytes. Furthermore, we found that mitogen induction of the interleukin-1 beta-converting enzyme (Ice) gene, a mammalian homolog of the Caenorhabditis elegans cell death gene ced-3, is also IRF-1-dependent. An IRF-1 binding sequence was identified in the 5' flanking region of the Ice gene. In addition, ectopic overexpression of IRF-1 results in the activation of the endogenous Ice gene and enhances the sensitivity of cells to radiation-induced apoptosis. Thus, induction of Ice gene may be involved in IRF-1 dependent DNA damage-induced apoptosis in activated mature T lymphocytes.
Tamura
T
T
Institute for Molecular and Cellular Biology, Osaka University, Japan.
Ishihara
M
M
Lamphier
M S
MS
Tanaka
N
N
Oishi
I
I
Aizawa
S
S
Matsuyama
T
T
Mak
T W
TW
Taki
S
S
Taniguchi
T
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D020170:Caspase 1; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D003208:Concanavalin A; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D005720:Gamma Rays; D050856:Interferon Regulatory Factor-1; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D007376:Interleukin-2; C494258:Irf1 protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D003208:Concanavalin A; D003546:Cysteine Endopeptidases; D020170:Caspase 1