Transcriptional Regulation of the TRAIL-R3 Gene

doi:10.1016/S0083-6729(04)67004-X

Vitamins & Hormones

Volume 67, 2004, Pages 51-63

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Abstract

TRAIL-R3 is a decoy receptor for TRAIL (tumor necrosis factor–related apoptosis-inducing ligand), a member of the tumor necrosis factor (TNF) ligand family. TRAIL induces apoptosis in a broad range of cancer cell lines, but not in many normal cells—a finding that generated extraordinary excitement about its potential as a specific antitumor agent. In several cell types, decoy receptors inhibit TRAIL-induced apoptosis by binding to it and preventing its binding to TRAIL proapoptotic or death receptors. However, recently published data regarding the role of these receptors in TRAIL-induced cellular death are contradictory. The key to resolving this controversy may lie in the regulation and cellular localization of TRAIL receptors. In this regard, cloning and analysis of the TRAIL-R3 promoter will help to identify the cellular factors that regulate its transcriptional expression. This chapter summarizes current knowledge in this field and outlines directions for future research.

Section snippets

Introduction: Trail and its Receptors

TRAIL (tumor necrosis factor–related apoptosis-inducing ligand) is a type II transmembrane protein (that is, it has an N-terminal cytoplasmic tail and a C-terminal extracellular domain) belonging to the TNF family (Wiley et al., 1995). Its extracellular domain can be proteolytically cleaved from the cell surface. Unlike other members of this family, TRAIL mRNA is expressed constitutively in most tissues of the human body (Wiley et al., 1995). TRAIL can selectively induce apoptosis in tumor

Decoy Receptors

TRAIL and CD95L, both members of the TNF superfamily, can bind to antiapoptotic receptors, also called decoy receptors. Two decoy receptors have been described for CD95L. DcR3 is a secreted receptor with four cysteine-rich subdomains and binds CD95L in competition with CD95 (Pitti et al., 1998). FDR (Fas⧸CD95 decoy receptor) is a membrane-bound receptor composed of the extracellular part of Fas, but lacking its intracellular domain (Jenkins et al., 2000).

TRAIL binds to two specific decoy

Future Directions

TRAIL and its complex receptor system, formed by widely expressed death and decoy receptors, present a complex picture that is far from being fully understood. Death and decoy receptors are often coexpressed within the same cell, giving rise to poor correlations between TRAIL receptor expression and TRAIL sensitivity. To explain the differential susceptibility to TRAIL-induced apoptosis, other factors must be taken into consideration. One such factor is the differential regulation of the death

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Transcriptional Regulation of the TRAIL-R3 Gene

Abstract

Section snippets

Introduction: Trail and its Receptors

Decoy Receptors

Future Directions

Cytokine Growth Factor Rev.

J. Biol. Chem.

Immunity

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Curr. Biol.

Mol. Ther.

J. Biol. Chem.

FEBS Lett.

FEBS Lett.

FEBS Lett.

J. Biol. Chem.

Exp. Cell Res.

Immunity

FEBS Lett.

FEBS Lett.

Constitutively active Akt1 protects HL60 leukemia cells from TRAIL-induced apoptosis through a mechanism involving NF-kappaB activation and cFLIP(L) up-regulation

Leukemia

Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer

Oncogene

To die or not to die—the quest of the TRAIL receptors

J. Leukocyte Biol.

Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family

J. Exp. Med.