Regulation of the human TRAIL gene

Abstract

TRAIL is a member of the TNF superfamily that induces tumor-selective cell death by engaging the pro-apoptotic death receptors DR4 and DR5. The antitumor potential of the TRAIL pathway has been targeted by several therapeutic approaches including recombinant TRAIL and TRAIL-receptor agonist antibodies among others. Interest in sensitizing tumor cells to TRAIL-mediated apoptosis has driven investigations of TRAIL-receptor gene regulation, though regulation of the TRAIL gene has been less studied. Physiologically, TRAIL serves as a pro-apoptotic effector molecule in the immune surveillance of cancer that is conditionally expressed by immune cells upon stimulation via an interferon-response element that was identified in early studies of the TRAIL gene promoter. Here, we map the TRAIL gene promoter and review studies of TRAIL gene regulation that involve several modalities of gene regulation including transcription factors, epigenetics, single-nucleotide polymorphisms and functionally distinct isoforms.

Figure 1. Crystal structure of TRAIL:DR5 complex. Homotrimeric DR5 (gray, light pink,and yellow) bound to homotrimeric TRAIL (cyan, green and magenta). A single zinc atom (green) is found in the center of the complex. Figure was generated using PyMOL software with Protein Data Bank (PBD) accession number 1D4V.

Figure 2. Apoptotic signaling induced by TRAIL. TRAIL initiates cell death by binding to the proapoptotic death receptors DR4 or DR5 that colocalizes their intracellular death domains. This clustering recruits the Fas-associated death domain (FADD) and pro-caspase-8 that results in its activation through autocatalytic cleavage. In type I cells, activate caspase-8 directly activates caspases-3, -6 and -7 to trigger the extrinsic cell death pathway. In type II cells, active caspase-8 cleaves Bid to a truncated form, tBid, which subsequently interacts with proapoptotic Bcl-2 family members Bax and Bak. This interaction leads to permeabilization of the mitochondrial membrane and release of cytochrome c. Cytosolic cytochrome c then combines with Apaf-1 and ATP to form the apoptosome that activates caspase-9 to trigger apoptosis through the caspase cascade.

Figure 3. Molecules that alter human TRAIL gene transcription. Interferons (IFN) activate TRAIL gene transcription through ISRE and IRFE sequences in the promoter region. Mutant HRAS (G12V) silences TRAIL gene expression through hypermethylation of CpG islands in the TRAIL gene promoter. Green arrows indicate activating relationships and the red lines indicate inhibitory relationships.

Figure 4. Sequence analysis of the human TRAIL gene promoter. Putative binding sites indicated by highlights above the appropriate sequences. Nucleotides contained in two or more putative binding sites are highlighted in red. Binding sites that have been empirically demonstrated to affect TRAIL promoter activity in experiment are bolded. Vertical lines below the sequence indicate SNPs. TRAIL sequence obtained from Accession number AF178756.

Figure 5. Genomic structure of human TRAIL variants. Exonic sequences of the full-length TRAIL are shown in green whereas novel sequences are shown in yellow.