The TRAIL decoy receptor TRUNDD (DcR2, TRAIL-R4) is induced by adenovirus-p53 overexpression and can delay TRAIL-, p53-, and KILLER/DR5-dependent colon cancer apoptosis

The cell surface decoy receptor proteins TRID (also known as DcR1 or TRAIL- R3) and TRUNDD (DcR2, TRAIL-R4) inhibit caspase-dependent cell death induce d by the cytotoxic ligand TRAIL in part because of their absent or truncate d cytoplasmic death domains, respectively. We previously identified the dea th domain containing proapoptotic TRAIL death receptor KILLER/DR5 (TRAIL-R2 ) as an upregulated transcript following exposure of cancer cells, with wil d-type but not with mutant or degraded p53 proteins, to a cytotoxic dose of adriamycin. In the present studies we provide evidence that expression of the TRAIL decoy receptors TRUNDD and TRID increases following infection of cancer cells with p53-expressing adenovirus (Ad-p53), in a manner similar t o other p53 target genes such as KILLER/DR5 and p27(WAF1/CIP1). Subsequent overexpression of TRUNDD in colon cancer cell lines caused a significant de lay in killing induced by TRAIL. Furthermore, cotransfection of TRUNDD with either p53 or KILLER/DR5 (at a 4:1 DNA ratio) in colon cancer cells decrea sed cell death caused by either gene. This protective effect of TRUNDD was not dependent on the presence of TRAIL, and overexpression of TRUNDD did no t alter the protein levels of either p53 or KILLER/DR5. Further deletion st udies showed that whereas protection by TRUNDD against TRAIL-mediated apopt osis did not require an intact intracellular domain (ICD), the first 43 ami no acids of the ICD of TRUNDD were needed for protection against cell death induced by p53 or KILLER/DR5. Our results suggest a model in which the TRA IL decoy receptors may be induced by p53, thereby attenuating an apoptotic response that appears to involve KILLER/DR5. Therefore, the p53-dependent i nduction of TRUNDD may provide a mechanism to transiently favor cell surviv al over cell death, and overexpression of TRUNDD may be another mechanism o f escape from p53-mediated apoptosis in gene therapy experiments.