TRAIL-beta and TRAIL-gamma: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL) without apoptotic potential.
Tumour necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL/APO2L) is a recently identified member of the TNF family, which induces programmed cell death in a variety of neoplastic cell types, but not in most nonneoplastic cells. In this study, we report on the identification of two novel alternative splice variants of TRAIL in neoplastic and non-neoplastic human cells lacking either exon 3 (TRAIL-beta) or exons 2 and 3 (TRAIL-gamma). In both splice variants, loss of exon 3 resulted in a frame shift generating a stop codon with consecutive extensive truncation in the extracellular domain. Ectopic expression revealed a loss of proapoptotic potential for both alternative splice variants. In contrast to the predominantly cytoplasmatic localisation of GFP-tagged TRAIL-alpha and TRAIL-beta, TRAIL-gamma showed an additional association with the cell surface and nuclear membrane. In conclusion, alternative splicing might be involved in fine tuning of TRAIL-induced apoptosis and underlines the complexity of the TRAIL system.
Krieg
A
A
Institute of Pathology, Heinrich Heine-University, Moorenstr. 5, Duesseldorf, Germany.
Krieg
T
T
Wenzel
M
M
Schmitt
M
M
Ramp
U
U
Fang
B
B
Gabbert
H E
HE
Gerharz
C D
CD
Mahotka
C
C
D017398:Alternative Splicing; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002292:Carcinoma, Renal Cell / Q000473:pathology; D003593:Cytoplasm / Q000737:chemistry; D005091:Exons; D016368:Frameshift Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000494:pharmacology; D008969:Molecular Sequence Data; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000494:pharmacology; D019014:fas Receptor
D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor