Regulation of the Fas apoptotic cell death pathway by Abl.
Relatively little is known about oncogene involvement in the regulation of Fas-mediated apoptosis. Inhibition of Fas-induced cell death by the bcl-2 oncogene has been demonstrated to be only partial. In light of a growing body of evidence for the Abl kinase as a negative regulator of cell death, we sought to determine whether Abl expression could protect against Fas-mediated cell death. To address this question, we utilized two separate strategies. In the first, we expressed human Fas in K562, a chronic myelogenous leukemia cell line, which constitutively expresses bcr-abl and examined the effects of Fas ligation in these cells. Fas-positive K562 transformants (K562.Fas) were found to be protected against Fas-mediated cell death. However, down-regulation of Bcr-Abl protein levels in K562.Fas cells using antisense oligonucleotides targeted to bcr-abl mRNA rendered these cells highly susceptible to Fas-induced death. In the second approach we utilized a Fas-positive HL-60 cell line, which we transfected with a temperature-sensitive mutant of v-Abl. HL-60.v-Ablts transfectants were found to be protected from Fas-induced apoptosis at the permissive but not the restrictive temperature for the Abl kinase. Taken together, these observations identify the Abl kinase as a negative regulator of Fas-mediated cell death. Since Abl was also found to block apoptosis mediated by ceramide, a recently proposed downstream effector of the apoptotic pathway initiated by Fas, we propose that Abl exerts its protective effects downstream of the early Fas-initiated signaling events.
McGahon
A J
AJ
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, California 92037, USA.
Nishioka
W K
WK
Martin
S J
SJ
Mahboubi
A
A
Cotter
T G
TG
Green
D R
DR
D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002518:Ceramides / Q000494:pharmacology; D004249:DNA Damage; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D016374:Oncogene Proteins v-abl / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor
D000954:Antigens, Surface; D002518:Ceramides; D016376:Oligonucleotides, Antisense; D016374:Oncogene Proteins v-abl; D019014:fas Receptor; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl