The antiapoptotic decoy receptor TRID/TRAIL-R3 is a p53-regulated DNA damage-inducible gene that is overexpressed in primary tumors of the gastrointestinal tract

Both DR4 and DR5 have recently been identified as membrane death receptors that are activated by their ligand TRAIL to engage the intracellular apopto tic machinery. TRID (also named as TRAIL-R3) is an antagonist decoy recepto r and lacks the cytoplasmic death domain, TRID protects from TRAIL-induced apoptosis by competing with DR4 and DR5 for binding to TRAIL, TRID has been shown to be overexpressed in normal human tissues but not in malignantly t ransformed cell lines. DR5 is a p53-regulated gene and me have recently rep orted that DR5 expression is induced in response to genotoxic stress in bot h a p53-dependent and independent manner (Sheikh et nl., 1998). In the curr ent study, we demonstrate that TRID gene expression is also induced by the genotoxic agents ionizing radiation and methyl methanesulfonate (MR IS) in predominantly p53 mild-type cells, whereas UV-irradiation does not induce T RID gene expression, Consistent with these results, exogenous wild-type p53 also upregulates the expression of endogenous TRID in p53-null cells. Thus , TRID appears to be a p53 target gene that is regulated by genotoxic stres s in a p53-dependent manner. Using primary gastrointestinal tract (GIT) tum ors and their matching normal tissue, we also demonstrate for the first tim e that TRID expression is enhanced in primary tumors of the GIT, It is, the refore, possible that TRID overexpressing GIT tumors may gain a selective g rowth advantage by escaping from TRAIL-induced apoptosis.