DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-kappa B and AP-1.
Apoptosis induced by DNA damage and other stresses can proceed via expression of Fas ligand (FasL) and ligation of its receptor, Fas (CD95). We report that activation of the two transcription factors NF-kappa B and AP-1 is crucially involved in FasL expression induced by etoposide, teniposide, and UV irradiation. A nondegradable mutant of I kappa B blocked both FasL expression and apoptosis induced by DNA damage but not Fas ligation. These stimuli also induced the stress-activated kinase pathway (SAPK/JNK), which was required for the maximal induction of apoptosis. A 1.2 kb FasL promoter responded to DNA damage, as well as coexpression with p65 Rel or Fos/Jun. Mutations in the relevant NF-kappa B and AP-1 binding sites eliminated these responses. Thus, activation of NF-kappa B and AP-1 contributes to stress-induced apoptosis via the expression of FasL.
Kasibhatla
S
S
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Brunner
T
T
Genestier
L
L
Echeverri
F
F
Mahboubi
A
A
Green
D R
DR
D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004249:DNA Damage / Q000276:immunology*; D053222:Fas Ligand Protein; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D008562:Membrane Glycoproteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics*
D000954:Antigens, Surface; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D019014:fas Receptor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases