A Short Nur77-Derived Peptide Converts Bcl-2 from a Protector to a Killer
Bcl-2 can be converted into a proapoptotic molecule by nuclear receptor Nur77. However, the development of Bcl-2 converters as anticancer therapeutics has not been explored. Here we report the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer,...
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| Veröffentlicht in: | Cancer cell 2008-10, Vol.14 (4), p.285-298 |
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| creator | Kolluri, Siva Kumar Zhu, Xiuwen Zhou, Xin Lin, Bingzhen Chen, Ya Sun, Kai Tian, Xuefei Town, James Cao, Xihua Lin, Feng Zhai, Dayong Kitada, Shinichi Luciano, Frederick O'Donnell, Edmond Cao, Yu He, Feng Lin, Jialing Reed, John C. Satterthwait, Arnold C. Zhang, Xiao-kun |
| description | Bcl-2 can be converted into a proapoptotic molecule by nuclear receptor Nur77. However, the development of Bcl-2 converters as anticancer therapeutics has not been explored. Here we report the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer, which induce apoptosis of cancer cells in vitro and in animals. The apoptotic effect of NuBCPs and their activation of Bax are not inhibited but rather potentiated by Bcl-2. NuBCP-9 and its enantiomer bind to the Bcl-2 loop, which shares the characteristics of structurally adaptable regions with many cancer-associated and signaling proteins. NuBCP-9s act as molecular switches to dislodge the Bcl-2 BH4 domain, exposing its BH3 domain, which in turn blocks the activity of antiapoptotic Bcl-X
L. |
| doi_str_mv | 10.1016/j.ccr.2008.09.002 |
| format | Article |
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L.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>bcl-2-Associated X Protein - genetics</subject><subject>bcl-2-Associated X Protein - metabolism</subject><subject>bcl-X Protein - metabolism</subject><subject>BH3 Interacting Domain Death Agonist Protein - metabolism</subject><subject>Binding Sites</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>CELLBIO</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>HUMDISEASE</subject><subject>Jurkat Cells</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, SCID</subject><subject>Neoplasms, Experimental - drug therapy</subject><subject>Neoplasms, Experimental - genetics</subject><subject>Neoplasms, Experimental - metabolism</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Nuclear Receptor Subfamily 4, Group A, Member 1</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - pharmacology</subject><subject>Peptide Fragments - pharmacology</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protein Structure, Tertiary</subject><subject>PROTEINS</subject><subject>Proto-Oncogene Proteins - pharmacology</subject><subject>Proto-Oncogene Proteins c-bcl-2 - chemistry</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Receptors, Steroid - genetics</subject><subject>Receptors, Steroid - metabolism</subject><subject>Stereoisomerism</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd1rFDEUxUNRbK3-AX2RPPk2483HZBIKhbp-FUtbUJ9DNnPHZpmdrEl2wf_elF1affEpN9xzfgnnEHLGoGXA1LtV631qOYBuwbQA_IicMN3rRiitntW5E12jGOhj8jLnFVQP680Lcsy0Fh0IdkKuLum3-5gKvdmmvm8-YAo7HOgdbkoYkC7ivMNUMn3vp4bTMcU1dfQuxYK-xERLrNevYZowvSLPRzdlfH04T8mPTx-_L74017efrxaX142X0pSGGz8CjLoT3BgnQTmplmypHePc69GDUr0Xg0S3lFyqToJjWsrOMOmE7AZxSi723M12ucbB41ySm-wmhbVLv210wf67mcO9_Rl3lleyUX0FvD0AUvy1xVzsOmSP0-RmjNtslVFCQWeqkO2FPsWcE46PjzCwDwXYla0F2IcCLBhbC6ieN3__7slxSLwKzvcCrBntAiabfcDZ4xBSzdQOMfwH_wcgjpSw</recordid><startdate>20081007</startdate><enddate>20081007</enddate><creator>Kolluri, Siva Kumar</creator><creator>Zhu, Xiuwen</creator><creator>Zhou, Xin</creator><creator>Lin, Bingzhen</creator><creator>Chen, Ya</creator><creator>Sun, Kai</creator><creator>Tian, Xuefei</creator><creator>Town, James</creator><creator>Cao, Xihua</creator><creator>Lin, Feng</creator><creator>Zhai, Dayong</creator><creator>Kitada, Shinichi</creator><creator>Luciano, Frederick</creator><creator>O'Donnell, Edmond</creator><creator>Cao, Yu</creator><creator>He, Feng</creator><creator>Lin, Jialing</creator><creator>Reed, John C.</creator><creator>Satterthwait, Arnold C.</creator><creator>Zhang, Xiao-kun</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081007</creationdate><title>A Short Nur77-Derived Peptide Converts Bcl-2 from a Protector to a Killer</title><author>Kolluri, Siva Kumar ; Zhu, Xiuwen ; Zhou, Xin ; Lin, Bingzhen ; Chen, Ya ; Sun, Kai ; Tian, Xuefei ; Town, James ; Cao, Xihua ; Lin, Feng ; Zhai, Dayong ; Kitada, Shinichi ; Luciano, Frederick ; O'Donnell, Edmond ; Cao, Yu ; He, Feng ; Lin, Jialing ; Reed, John C. ; Satterthwait, Arnold C. ; Zhang, Xiao-kun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c449t-29cf00f853299a406a46b1b8a122c8fc0667c3d4eab4246540a18445914a345d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>bcl-2-Associated X Protein - genetics</topic><topic>bcl-2-Associated X Protein - metabolism</topic><topic>bcl-X Protein - metabolism</topic><topic>BH3 Interacting Domain Death Agonist Protein - metabolism</topic><topic>Binding Sites</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>CELLBIO</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>HUMDISEASE</topic><topic>Jurkat Cells</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, SCID</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>Neoplasms, Experimental - genetics</topic><topic>Neoplasms, Experimental - metabolism</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Nuclear Receptor Subfamily 4, Group A, Member 1</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - pharmacology</topic><topic>Peptide Fragments - pharmacology</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protein Structure, Tertiary</topic><topic>PROTEINS</topic><topic>Proto-Oncogene Proteins - pharmacology</topic><topic>Proto-Oncogene Proteins c-bcl-2 - chemistry</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Receptors, Steroid - genetics</topic><topic>Receptors, Steroid - metabolism</topic><topic>Stereoisomerism</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kolluri, Siva Kumar</creatorcontrib><creatorcontrib>Zhu, Xiuwen</creatorcontrib><creatorcontrib>Zhou, Xin</creatorcontrib><creatorcontrib>Lin, Bingzhen</creatorcontrib><creatorcontrib>Chen, Ya</creatorcontrib><creatorcontrib>Sun, Kai</creatorcontrib><creatorcontrib>Tian, Xuefei</creatorcontrib><creatorcontrib>Town, James</creatorcontrib><creatorcontrib>Cao, Xihua</creatorcontrib><creatorcontrib>Lin, Feng</creatorcontrib><creatorcontrib>Zhai, Dayong</creatorcontrib><creatorcontrib>Kitada, Shinichi</creatorcontrib><creatorcontrib>Luciano, Frederick</creatorcontrib><creatorcontrib>O'Donnell, Edmond</creatorcontrib><creatorcontrib>Cao, Yu</creatorcontrib><creatorcontrib>He, Feng</creatorcontrib><creatorcontrib>Lin, Jialing</creatorcontrib><creatorcontrib>Reed, John C.</creatorcontrib><creatorcontrib>Satterthwait, Arnold C.</creatorcontrib><creatorcontrib>Zhang, Xiao-kun</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kolluri, Siva Kumar</au><au>Zhu, Xiuwen</au><au>Zhou, Xin</au><au>Lin, Bingzhen</au><au>Chen, Ya</au><au>Sun, Kai</au><au>Tian, Xuefei</au><au>Town, James</au><au>Cao, Xihua</au><au>Lin, Feng</au><au>Zhai, Dayong</au><au>Kitada, Shinichi</au><au>Luciano, Frederick</au><au>O'Donnell, Edmond</au><au>Cao, Yu</au><au>He, Feng</au><au>Lin, Jialing</au><au>Reed, John C.</au><au>Satterthwait, Arnold C.</au><au>Zhang, Xiao-kun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Short Nur77-Derived Peptide Converts Bcl-2 from a Protector to a Killer</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2008-10-07</date><risdate>2008</risdate><volume>14</volume><issue>4</issue><spage>285</spage><epage>298</epage><pages>285-298</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Bcl-2 can be converted into a proapoptotic molecule by nuclear receptor Nur77. However, the development of Bcl-2 converters as anticancer therapeutics has not been explored. Here we report the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer, which induce apoptosis of cancer cells in vitro and in animals. The apoptotic effect of NuBCPs and their activation of Bax are not inhibited but rather potentiated by Bcl-2. NuBCP-9 and its enantiomer bind to the Bcl-2 loop, which shares the characteristics of structurally adaptable regions with many cancer-associated and signaling proteins. NuBCP-9s act as molecular switches to dislodge the Bcl-2 BH4 domain, exposing its BH3 domain, which in turn blocks the activity of antiapoptotic Bcl-X
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| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects bcl-2-Associated X Protein - genetics bcl-2-Associated X Protein - metabolism bcl-X Protein - metabolism BH3 Interacting Domain Death Agonist Protein - metabolism Binding Sites Cell Proliferation - drug effects Cell Survival - drug effects CELLBIO DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Female HeLa Cells Humans HUMDISEASE Jurkat Cells Mice Mice, Knockout Mice, SCID Neoplasms, Experimental - drug therapy Neoplasms, Experimental - genetics Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Nuclear Receptor Subfamily 4, Group A, Member 1 Oligopeptides - chemistry Oligopeptides - pharmacology Peptide Fragments - pharmacology Protein Binding Protein Conformation Protein Structure, Tertiary PROTEINS Proto-Oncogene Proteins - pharmacology Proto-Oncogene Proteins c-bcl-2 - chemistry Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Receptors, Steroid - genetics Receptors, Steroid - metabolism Stereoisomerism Time Factors Transfection Xenograft Model Antitumor Assays |
| title | A Short Nur77-Derived Peptide Converts Bcl-2 from a Protector to a Killer |
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