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Evidence that the death receptor DR4 is a DNA damage‐inducible, p53‐regulated gene
Author(s) -
Guan Baoxiang,
Yue Ping,
Clayman Gary L.,
Sun ShiYong
Publication year - 2001
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.1101
Subject(s) - dna damage , transfection , biology , receptor , microbiology and biotechnology , apoptosis , dna repair , tumor necrosis factor alpha , mutant , wild type , dna , gene , cancer research , immunology , genetics
Abstract DR4 (TRAIL‐R1), a member of the tumor necrosis factor receptor superfamily, is a cell surface receptor that triggers the apoptotic machinery upon binding to its ligand tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL). Although three other TRAIL receptors DR5, DcR1, and DcR2 are induced by DNA damage and are regulated by the wild‐type p53 tumor suppressor, it was not known whether these factors also affect DR4 expression. In this study, we found that DR4 expression is also enhanced by DNA damage whether induced by ionizing radiation or by chemotherapeutic agents. The induction was observed predominantly in cells containing wild‐type p53 and was similar to the regulation patterns of DR5 and Fas, two other members of the family which are known to be regulated by p53. Transfection of HPV 16 E6 gene into cells with wild‐type p53, which decreased the level of p53 protein, resulted in suppression of DR4 induction by DNA‐damaging agents. Conversely, introduction of exogenous wild‐type p53 through adenovirus infection has led to upregulation of endogenous DR4 in cells with mutant p53. Moreover, the transcription inhibitor actinomycin D abolished DNA‐damaging agent‐induced DR4 expression. Thus, DR4 appears to be a DNA damage‐inducible, p53‐regulated gene. © 2001 Wiley‐Liss, Inc.