Interferon-gamma-induced apoptotic responses of Fanconi anemia group C hematopoietic progenitor cells involve caspase 8-dependent activation of caspase 3 family members.
Hematopoietic progenitor cells (HPC) from mice nullizygous at the Fanconi anemia (FA) group C locus and children with Fanconi anemia group C (FA-C) are hypersensitive to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha. This hypersensitivity results, in part, from the capacity of these cytokines to prime the fas pathway. Because fas-mediated programmed cell death in many cells involves sequential activation of specific caspases, we tested the hypothesis that programmed cell death in FA HPC involves the ordered activation of specific caspase molecules. Lysates from lymphoblasts treated with both agonistic anti-fas antibody and IFN-gamma contained activated caspase 3 family members (caspases 3, 6, and 7), as well as caspase 8, whereas activation of caspases 1, 2, 4, 9, and 10 was not detected. The apoptotic effects of fas agonists in IFN-gamma-treated human and murine FA-C cells were blocked when pretreated with inhibitors (ac-DEVD-cho, CP-DEVD-cho, Z-DEVD-FMK) of the caspase 3 protease. Inhibitors (ac-YVAD-cho, CP-YVAD-cho, Z-YVAD-FMK) of caspase 1 did not block apoptosis or caspase 3 activation. Treatment of FA cells with the fluoromethyl ketone tetrapeptide caspase 8 inhibitor (ac-IETD-FMK) did suppress caspase 3 activation. A 4-fold greater fraction of IFN-induced FA-C cells expressed caspase 3 than FA-C cells complemented by retroviral-mediated transfer of FANCC. Therefore fas-induced apoptosis in Fanconi anemia cells of the C type involves the activation of caspase 8, which controls activation of caspase 3 family members and one direct or indirect function of the FANCC protein is to suppress apoptotic responses to IFN-gamma upstream of caspase 3 activation. (Blood. 2000;96:4204-4211)
Rathbun
R K
RK
Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland, OR, USA.
Christianson
T A
TA
Faulkner
G R
GR
Jones
G
G
Keeble
W
W
O'Dwyer
M
M
Bagby
G C
GC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow / Q000473:pathology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism* / Q000502:physiology*; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002648:Child; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects; D005199:Fanconi Anemia / Q000235:genetics / Q000473:pathology*; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D018740:Genetic Heterogeneity; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D014162:Transfection; D019014:fas Receptor / Q000502:physiology
D061945:Caspase Inhibitors; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D007527:Isoenzymes; D009687:Nuclear Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D019014:fas Receptor; D007371:Interferon-gamma; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases