Evidence that the human death receptor 4 is regulated by activator protein 1

B Guan, P Yue, R Lotan, SY Sun - Oncogene, 2002 - nature.com
B Guan, P Yue, R Lotan, SY Sun
Oncogene, 2002nature.com
Abstract 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 …
Abstract
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.
nature.com