Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) decoy receptor TRAIL-R3 is up-regulated by p53 in breast tumor cells through a mechanism involving an intronic p53-binding site.
Tumor necrosis factor-related apoptosis-inducing ligand receptor 3 (TRAIL-R3) is a decoy receptor for TRAIL, a member of the tumor necrosis factor family. In several cell types decoy receptors inhibit TRAIL-induced apoptosis by binding TRAIL and thus preventing its binding to proapoptotic TRAIL receptors. We studied the regulation of TRAIL-R3 gene expression in breast tumor cells treated with the genotoxic drug doxorubicin (DXR). The breast tumor cell line MCF-7 (p53 wild type) responded to DXR with a marked elevation of TRAIL-R3 expression at the mRNA, total protein, and cell surface levels. In contrast, in EVSA-T cells (p53 mutant) DXR did not induce increased expression of TRAIL-R3. In MCF-7 cells overexpressing the human papillomavirus protein E6, which causes p53 degradation, DXR-induced TRAIL-R3 expression was notably reduced. Furthermore, in MCF-7 cells overexpressing a temperature-sensitive p53 mutant (Val135), shifting the cultures to the permissive temperature was sufficient to induce the expression of TRAIL-R3. We also cloned and characterized a p53 consensus element located within the first intron of the human TRAIL-R3 gene. This element binds p53 and confers responsiveness to genotoxic damage to constructs of the TRAIL-R3 promoter in transient transfection experiments. Our results indicate that genotoxic treatments such as DXR, frequently used in cancer therapy, may also induce genes such as TRAIL-R3 that potentially have antiapoptotic actions and thus interfere with the TRAIL signaling system. This is particularly important in view of the proposed use of TRAIL in antitumor therapy.
Ruiz de Almodóvar
Carmen
C
Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Cientificas (CSIC), calle Ventanilla 11, 18001 Granada.
Ruiz-Ruiz
Carmen
C
Rodríguez
Antonio
A
Ortiz-Ferrón
Gustavo
G
Redondo
Juan Miguel
JM
López-Rivas
Abelardo
A
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D016384:Consensus Sequence; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007438:Introns; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D014162:Transfection; D053319:Tumor Necrosis Factor Decoy Receptors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D058851:GPI-Linked Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C108661:TNFRSF10C protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin