Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5
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....
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| Veröffentlicht in: | Apoptosis (London) 2009-06, Vol.14 (6), p.778-787 |
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| creator | Gasparian, Marine E Chernyak, Boris V Dolgikh, Dmitry A Yagolovich, Anne V Popova, Ekaterina N Sycheva, Anna M Moshkovskii, Sergey A Kirpichnikov, Mikhail P |
| description | 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. |
| doi_str_mv | 10.1007/s10495-009-0349-3 |
| format | Article |
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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.</description><identifier>ISSN: 1360-8185</identifier><identifier>EISSN: 1573-675X</identifier><identifier>DOI: 10.1007/s10495-009-0349-3</identifier><identifier>PMID: 19412666</identifier><language>eng</language><publisher>Boston: Boston : Springer US</publisher><subject>Amino Acid Substitution - drug effects ; Apoptosis - drug effects ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell Biology ; Cell Line, Tumor ; Cytochalasin D - pharmacology ; E coli ; Humans ; Kinetics ; Mutant Proteins - metabolism ; Mutants ; Mutation - genetics ; Oncology ; Original Paper ; Paclitaxel - pharmacology ; Protein Binding - drug effects ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; Surface Plasmon Resonance ; TNF-Related Apoptosis-Inducing Ligand - metabolism ; Ultracentrifugation ; Virology</subject><ispartof>Apoptosis (London), 2009-06, Vol.14 (6), p.778-787</ispartof><rights>Springer Science+Business Media, LLC 2009</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c393t-fd604bacc08fa511c680cd2072707dba851abb0a00e4ef2fec3753253ac8b10b3</citedby><cites>FETCH-LOGICAL-c393t-fd604bacc08fa511c680cd2072707dba851abb0a00e4ef2fec3753253ac8b10b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10495-009-0349-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10495-009-0349-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19412666$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gasparian, Marine E</creatorcontrib><creatorcontrib>Chernyak, Boris V</creatorcontrib><creatorcontrib>Dolgikh, Dmitry A</creatorcontrib><creatorcontrib>Yagolovich, Anne V</creatorcontrib><creatorcontrib>Popova, Ekaterina N</creatorcontrib><creatorcontrib>Sycheva, Anna M</creatorcontrib><creatorcontrib>Moshkovskii, Sergey A</creatorcontrib><creatorcontrib>Kirpichnikov, Mikhail P</creatorcontrib><title>Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5</title><title>Apoptosis (London)</title><addtitle>Apoptosis</addtitle><addtitle>Apoptosis</addtitle><description>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.</description><subject>Amino Acid Substitution - drug effects</subject><subject>Apoptosis - drug effects</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cytochalasin D - pharmacology</subject><subject>E coli</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Mutant Proteins - metabolism</subject><subject>Mutants</subject><subject>Mutation - genetics</subject><subject>Oncology</subject><subject>Original Paper</subject><subject>Paclitaxel - pharmacology</subject><subject>Protein Binding - drug effects</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Receptors, 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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.</abstract><cop>Boston</cop><pub>Boston : Springer US</pub><pmid>19412666</pmid><doi>10.1007/s10495-009-0349-3</doi><tpages>10</tpages></addata></record> |
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| ispartof | Apoptosis (London), 2009-06, Vol.14 (6), p.778-787 |
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| subjects | Amino Acid Substitution - drug effects Apoptosis - drug effects Biochemistry Biomedical and Life Sciences Biomedicine Cancer Research Cell Biology Cell Line, Tumor Cytochalasin D - pharmacology E coli Humans Kinetics Mutant Proteins - metabolism Mutants Mutation - genetics Oncology Original Paper Paclitaxel - pharmacology Protein Binding - drug effects Proto-Oncogene Proteins c-bcl-2 - metabolism Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism Surface Plasmon Resonance TNF-Related Apoptosis-Inducing Ligand - metabolism Ultracentrifugation Virology |
| title | Generation of new TRAIL mutants DR5-A and DR5-B with improved selectivity to death receptor 5 |
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