Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5 |
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Authors: | Marine E Gasparian Boris V Chernyak Dmitry A Dolgikh Anne V Yagolovich Ekaterina N Popova Anna M Sycheva Sergey A Moshkovskii Mikhail P Kirpichnikov |
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Institution: | (1) Laboratory of Protein Engineering, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, RAS, 16/10 Miklukho-Maklaya, 117997 Moscow, Russia;(2) A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119899 Moscow, Russia;(3) V. N. Orekhovich Institute of Biomedical Chemistry, RAMS, 119121 Moscow, Russia |
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Abstract: | TRAIL (tumor necrosis factor (TNF) related apoptosis-inducing ligand) has been introduced as an extrinsic pathway inducer
of apoptosis that does not have the toxicities of Fas and TNF. However, the therapeutic potential of TRAIL is limited because
of many primary tumor cells are resistant to TRAIL. Despite intensive investigations, little is known in regards to the mechanisms
underlying TRAIL selectivity and efficiency. A major reason likely lies in the complexity of the interaction of TRAIL with
its five receptors, of which only two DR4 and DR5 are death receptors. Binding of TRAIL with decoy receptors DcR1 and DcR2
or soluble receptor osteoprotegerin (OPG) fail to induce apoptosis. Here we describe design and expression in Escherichia coli of DR5-selective TRAIL variants DR5-A and DR5-B. The measurements of dissociation constants of these mutants with all five
receptors show that they practically do not interact with DR4 and DcR1 and have highly reduced affinity to DcR2 and OPG receptors.
These mutants are more effective than wild type TRAIL in induction of apoptosis in different cancer cell lines. In combination
with the drugs targeted to cytoskeleton (taxol, cytochalasin D) the mutants of TRAIL induced apoptosis in resistant Hela cells
overexpressing Bcl-2. The novel highly selective and effective DR5-A and DR5-B TRAIL variants will be useful in studies on
the role of different receptors in TRAIL-induced apoptosis in sensitive and resistant cell lines.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | TRAIL Apoptosis Death receptors Decoy receptors |
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