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TRAIL |
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Figure 6-G-3. Schematic drawing of TRAIL
receptors, which can be divided into two categories:
TRAIL (TNF-related apoptosis-inducing ligand) is a protein consisting of 281 amino acids. It is also called APO-2L. Five TRAIL receptors have been identified (above figure). Two of them can lead to apoptosis. The other three serve as "decoy" receptors. A cell expressing more decoy receptors is more likely to survive upon binding of the death ligands. TRAIL as Cancer Therapeutic TRAIL has been demonstrated to kill a wide variety of tumor cells with minimal effects on normal cells. This is because TRAIL's death receptors (TRAIL-R1 and TRAIL-R2) are mainly expressed in transformed cells while its decoy receptors (TRAIL-R3, TRAIL-R4 and TRAIL-R5) are expressed in normal cells. The major concern about using TRAIL as a therapeutic is its toxicity to human hepatocytes. TRAIL can cause significant death of normal human hepatocytes, but has no effect on the normal hepatocytes of mice. In the future, as we have better understanding on the regulation of receptor expression and signaling cascades, it may be possible to save normal cells from the toxic effects of TRAIL. TRAIL and AIDS AIDS (acquired immune deficiency syndrome) is characterized by the depletion of T cells. It has been demonstrated that HIV can induce apoptosis in both infected cells and their neighboring (bystander) cells (review). Recently, it was further shown that those bystander cells were killed mainly through the TRAIL-mediated apoptosis. Experimental results suggest that the extracellular Tat protein, released from HIV-infected cells, can induce production of TRAIL by macrophages, resulting in the apoptosis of bystander T cells (reference). As mentioned above, TRAIL has minimal effects on normal cells (except for
human hepatocytes). Then, how could T cells in HIV patients become
susceptible to TRAIL? Presumably, the regulation of TRAIL receptor
expression in
bystander cells should be altered, but the detailed mechanism is not
known. A recent
report indicates that the HIV's surface protein, gp120, is
involved.
Review Articles: Tissue Distribution of the Death Ligand TRAIL and Its Receptors - J. Histochemistry and Cytochemistry, 2004.
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