Evidence that the death receptor DR4 is a DNA damage-inducible, p53-regulated gene

DR4 (TRAIL-R1), a member of the tumor necrosis factor receptor superfamily, is a cell surface receptor that triggers the apoptotic machinery upon bind ing to its: ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Although three other TRAIL receptors DR5, DcR1, and DcR2 are induc ed by DNA damage and are regulated by the wild-type p53 tumor suppressor, i t was not known whether these factors also affect DR4 expression. In this s tudy, we found that DR4 expression is also enhanced by DNA damage whether i nduced by ionizing radiation or by chemotherapeutic agents. The induction w as observed predominantly in cells containing wild-type p53 and was similar to the, regulation patterns of DR5 and Fas, two other members of the famil y which are known to be regulated by p53. Transfection of HPV 16 E6 gene in to cells with wild-type p57, which decreased the level of p53 protein, resu lted in suppression of DR4 induction by DNA-damaging agents. Conversely, in troduction of exogenous wild-type p53 through adenovirus infection has led to upregulation of endogenous DR4 in cells with mutant p53. Moreover, the t ranscription inhibitor actinomycin D abolished DNA-damaging agent-induced D R4 expression. Thus, DR4 appears to be a DNA damage-inducible, p53-regulate d gene. (C) 2001 Wiley-Liss, Inc.