LUCA-15/RBM5 is a putative tumour suppressor. The gene encodes a number of alternative RNA splice variants with differing abilities to either enhance or suppress apoptosis, and it is likely that this ability to modulate apoptosis is central to the putative tumour suppressor activity of LUCA-15. This report demonstrates for the first time that expression from the LUCA-15 locus modulates apoptosis triggered by the death-inducing ligand TRAIL. Using Jurkat T lymphoblastic leukemia cells, LUCA-15 expression was shown to enhance not only TRAIL but TNF-α- and Fas-mediated apoptosis. LUCA-15, therefore, has the ability to lower the apoptotic threshold of multiple receptor-initiated death-inducing signals. Of note, sensitisation of the Jurkat cells to TRAIL was shown to depend on new protein synthesis, since no enhancement of apoptosis was observed when cells were exposed to both TRAIL and the protein synthesis inhibitor cycloheximide. This result suggests that LUCA-15 does not act independently to regulate apoptosis, but modulates a process that requires additional, newly synthesized protein. These results may explain the putative role of LUCA-15 as a tumour suppressor, suggesting that lack of functional LUCA-15 could provide the means by which malignant T cells escape receptor-initiated apoptotic signals.