Evidence that the human death receptor 4 is regulated by activator protein 1.
Death receptor 4 (DR4; also called 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 several chemotherapeutic agents were reported to induce DR4 expression, the mechanism of this effect remains largely unknown. To begin to understand its regulation, we cloned a 1.8 Kb 5'-flanking region of the human DR4 gene and identified several putative binding sites for transcription factors including activator protein 1 (AP-1). Among the three putative AP-1 binding sites, the site located at -350/-344 is functionally active as evidenced by a combination of electrophoretic mobility shift and luciferase reporter assays. The AP-1 activator phorbol 12-myristate 13-acetate (TPA) enhanced the binding of this DR4 AP-1 binding site to protein(s) in a nuclear extract from TPA-treated cells, increased luciferase activity of a reporter construct containing this site and induced DR4 expression at the transcription level. These results indicate that AP-1 regulates DR4 expression via the AP-1 binding site located at -350/-344. AP-1 has been implicated in many critical cellular processes including apoptosis, and is a major target of the c-Jun NH(3)-terminal kinase signaling pathway that is activated by many anticancer drugs. Therefore, our findings may increase the understanding of the mechanisms underlying AP-1-mediated apoptosis as well as drug-induced apoptosis.
Guan
Baoxiang
B
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yue
Ping
P
Lotan
Reuben
R
Sun
Shi-Yong
SY
D020121:5' Untranslated Regions / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000502:physiology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D020121:5' Untranslated Regions; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D013755:Tetradecanoylphorbol Acetate