Figure 7.

LARD/TNFRSF12/DR3/Apo3 expression correlates with PTC⁺ status. LARD is an alternatively spliced death-domain-containing member of the tumor necrosis factor receptor family (TNFR). However, only the major splice variant (isoform 1) contains the death domain and is capable of inducing apoptosis. The splicing distribution of LARD isoforms has been shown to change on lymphocyte activation, suggesting that alternative splicing may be a control point regulating lymphocyte proliferation [55]. (a) Screaton et al. [55] showed that, before lymphocyte activation, only LARD isoforms 2, 3, 4, 5 and 6 are expressed. Primary blood lymphocytes treated with an activating agent were found instead to express the major, apoptosis-promoting splice variant (isoform 1) almost exclusively. This panel is reproduced with permission from Figure 6a of [55] (^© National Academy of Sciences). Screaton et al. [55] describe their figure as follows: "Southern blots of reverse transcriptase-PCR of LARD cDNA with primers F LARD Kpn and R LARD Xba probed with 32P-labeled primer F LARD Xba. Lanes: 1, CD4⁺ cells; 2, CD8⁺ cells; 3, B cells; 4 PHA-blasted PBL; 5, negative control." (b) LARD isoforms 2, 3, 4, 5 and 6 were found in our analysis of SWISS-PROT to have PTCs, rendering them potential targets of NMD. The precise correlation between LARD isoform expression and PTC⁺ status hints that there may be a role for alternative-splicing-induced NMD. Here, the gene structures of these five isoforms are shown alongside that of the full-length LARD isoform (isoform 1). In each case, the location of the stop codon has been labeled and, where appropriate, isoforms have been denoted as PTC⁺.