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

Oncogene. 2002 May 9;21(20):3121-9. doi: 10.1038/sj.onc.1205430.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Antineoplastic Agents / pharmacology
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Base Sequence
  • Binding Sites
  • Cloning, Molecular
  • Gene Expression Regulation / drug effects
  • Genes, Reporter
  • Humans
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • Membrane Glycoproteins / physiology
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Protein Binding / drug effects
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / physiology*
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / genetics
  • Regulatory Sequences, Nucleic Acid
  • Signal Transduction / drug effects
  • TNF-Related Apoptosis-Inducing Ligand
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / physiology*
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • 5' Untranslated Regions
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Membrane Glycoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFSF10 protein, human
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Luciferases
  • Tetradecanoylphorbol Acetate

Associated data

  • GENBANK/AY033911