Possible attenuation of fas-mediated signaling by dominant expression of caspase-8 aberrant isoform in adult T-cell leukemia cells.

The Fas up-regulated in adult T-cell leukemia (ATL) cells is usually the wild-type protein and is usually functional, at least in vitro. However, primary ATL cells, in contrast to ATL cell lines, are not necessarily susceptible to anti-Fas-induced apoptosis. To clarify the mechanism tuning the apoptotic signal transduction initiated by the activation caspase-8 in ATL cells and ATL cell lines, we examined the expression profile of caspase-8, of which there are at least 8 isoforms at the messenger RNA (mRNA) level with the potential to finely tune the signal transduction. Reverse transcription polymerase chain reaction disclosed the 2 major mRNA bands of 815 bp (casp-8S) and 951 bp (casp-8L) with different expression profiles among normal CD4 T-cells, primary ATL cells, and ATL cell lines. Casp-8L was the predominant form in primary ATL cells, whereas casp-8S was predominant in ATL cell lines. Casp-8S was structurally intact as shown by nucleotide analysis, whereas casp-8L was shown to be generated by a 136-bp insertion between exons 8 and 9 and to carry a frame shift in the transcript, introducing a premature stop codon and probably resulting in a truncated protein of approximately 30 kd deduced for the casp-8L transcript. These results suggest that an imbalanced expression of casp-8 isoforms, especially the dominant casp-8L in primary ATL cells, is in part responsible for tumor pathology through the modulation of cell death via Fas-mediated signaling.