Alternative splicing of caspase-8 mRNA during differentiation of human leukocytes.
Caspase-8 is a key initiator of death receptor-induced apoptosis. Here we provide evidence that caspase-8 expression is subject to posttranscriptional regulation in human leukocytes. Resting peripheral blood lymphocytes preferentially use a distant splice donor site at the 3'-end of caspase-8 exon 8 to generate mRNAs with a truncated open reading frame. When lymphocytes were activated, the expression of caspase-8 variants was shifted to caspase-8/a and b which lack the extension of exon 8. The opposite change of the splicing pattern was found in a neutrophil differentiation model. Promyelocytic HL-60 cells mainly expressed caspase-8 mRNAs with the normal exon 8, but the splicing pattern was changed to the distant exon 8 splice site during DMSO-induced differentiation of HL-60 cells. In spite of the presence of these novel mRNAs, the corresponding translation products were not detectable in either cell type. Our findings suggest that leukocyte differentiation and alternative splicing of caspase-8 pre-mRNA are inter-dependent processes.
Eckhart
L
L
Department of Dermatology, University of Vienna Medical School, Vienna, A-1090, Austria.
Henry
M
M
Santos-Beneit
A M
AM
Schmitz
I
I
Krueger
A
A
Fischer
H
H
Bach
J
J
Ban
J
J
Kirchhoff
S
S
Krammer
P H
PH
Mollinedo
F
F
Tschachler
E
E
D017398:Alternative Splicing; D017209:Apoptosis; D001483:Base Sequence; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005091:Exons; D014644:Genetic Variation; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*
D012333:RNA, Messenger; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D004121:Dimethyl Sulfoxide