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.

摘要

Evidence suggests that the death receptor gene KILLER/ DR5 (TRAIL-R4), which binds the TNF-related ligand TRAIL (TNF-Related Apoptosis-Inducing Ligand), is regulated by the p53 tumor suppressor gene, providing a link between p53-mediated apoptosis and death-receptor signaling. TRAIL-mediated apoptosis, in turn, also seems to be regulated by anti-apoptotic decoy receptors, DcR1 (TRAIL-R3, TRID) and DcR2 (TRAIL-R4, TRUNDD); however, the effects of p53 on the decoy receptors remain unknown. The present study now reports that DcR2 mRNA and protein can be induced by p53 overexpression generated by Ad-p53 infection in a panel of tumor cell lines and also by stabilization of endogenous wild-type p53 following treatment of cell lines with DNA-damaging agents or apoptosis-inducing drugs. The overexpression of DcR2 protected cells from not only TRAIL-mediated apoptosis but also from p53-mediated apoptosis. This effect appeared to be mediated by KILLER/DR5 as overexpression of DcR2 also protected against KILLER/DR5-mediated apoptosis in colon cancer cell lines. It was then determined which region of DcR2, the extracellular domain (ECD) or the intracellular domain (ICD), mediated this protection through the construction of deletion mutants. Whereas deletion of the ICD of DcR2 did not decrease the ability of the receptor to protect against TRAIL-mediated apoptosis, the first 43 amino-acids of the ICD were required for protection. Although overexpression of DcR2 did not activate NF-κB activity, DcR2 seems to be able to interfere with the ability of p53 to activate luciferase reporters that encode p53-binding sites from p53, KILLER/DR5, or bax. The expression of the pro-survival protein FLIP is also elevated in cell lines with stable overexpression of DcR2. Finally, this study also provides evidence that KILLER/DR5 and DcR2 can be induced at the mRNA and protein levels independent of wild-type p53 status following treatment of cell lines with apoptosis-inducing agents. In conclusion, the anti-apoptotic TRAIL receptor DcR2 may represent a novel target of p53 that may function as another checkpoint in p53-mediated apoptosis. Whether these protective mechanisms are also altered in human tumorigenesis remain to be seen.