Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA
Expression of mutant p53 correlates with poor prognosis in many tumors, therefore strategies aimed at reactivation of mutant p53 are likely to provide important benefits for treatment of tumors that are resistant to chemotherapy and radiotherapy. We have previously identified and characterized a sma...
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| Veröffentlicht in: | Cell cycle (Georgetown, Tex.) Tex.), 2010-05, Vol.9 (9), p.1847-1855 |
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| creator | Zhao, Carolyn Y. Grinkevich, Vera Nikulenkov, Fedor Bao, Wenjie Selivanova, Galina |
| description | Expression of mutant p53 correlates with poor prognosis in many tumors, therefore strategies aimed at reactivation of mutant p53 are likely to provide important benefits for treatment of tumors that are resistant to chemotherapy and radiotherapy. We have previously identified and characterized a small molecule RITA that binds p53 and induces a conformational change which prevents the binding to p53 of several inhibitors, including its own destructor MDM2. In this way, RITA rescues the tumor suppression function of wild type p53. Here, we demonstrate that RITA suppressed the growth and induced apoptosis in human tumor cell lines of a diverse origin carrying mutant p53 proteins. RITA restored transcriptional transactivation and transrepression function of several hot spot p53 mutants. The ability of RITA to rescue the activity of different p53 mutants suggests the generic mechanism of action. Thus, RITA is a promising lead for the development of anti-cancer drugs that reactivate the tumor suppressor function of p53 in cancer cells irrespective whether they express mutant or wild type p53. |
| doi_str_mv | 10.4161/cc.9.9.11545 |
| format | Article |
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We have previously identified and characterized a small molecule RITA that binds p53 and induces a conformational change which prevents the binding to p53 of several inhibitors, including its own destructor MDM2. In this way, RITA rescues the tumor suppression function of wild type p53. Here, we demonstrate that RITA suppressed the growth and induced apoptosis in human tumor cell lines of a diverse origin carrying mutant p53 proteins. RITA restored transcriptional transactivation and transrepression function of several hot spot p53 mutants. The ability of RITA to rescue the activity of different p53 mutants suggests the generic mechanism of action. 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Thus, RITA is a promising lead for the development of anti-cancer drugs that reactivate the tumor suppressor function of p53 in cancer cells irrespective whether they express mutant or wild type p53.</description><subject>Apoptosis</subject><subject>Binding</subject><subject>Biology</subject><subject>Bioscience</subject><subject>Calcium</subject><subject>Cancer</subject><subject>Cell</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cycle</subject><subject>Furans - therapeutic use</subject><subject>Humans</subject><subject>Landes</subject><subject>Mutation</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - radiotherapy</subject><subject>Organogenesis</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Transcriptional Activation</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>1538-4101</issn><issn>1551-4005</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0E1vFSEUBuCJsbG1unNt2LlxWhhgPpbNTdUmjSZNu-mGMGcOFmVghJk099_LONe7MjEsIOTh5eQtineMXghWs0uAiy4vxqSQL4ozJiUrBaXy5XrmbSkYZafF65R-UFq1TcdeFacVFbzmlJ0VX-8wwYIkGDI_IdFTmOYwWyitHxaw_jsxi4fZBr-ScZm1n8kkOen3JI3aOTIGh7A4JHc391dvihOjXcK3h_28ePh0fb_7Ut5--3yzu7otQXR8LjlH2dds4G2LZqiEaUwFgpq656bpO961tBGt6CW0vDGcNVIa2vFqACqBCcHPi3LLTc84Lb2aoh113KugrTpc_cwnVLmNuqqy_7D5KYZfC6ZZjTYBOqc9hiWphnPGKipX-XGTEENKEc0xm1G1Fq4AVJfXn8Izf38IXvoRhyP-23AGdAP5qwFTb0MCix7wSHOejrlyh8fM8j9PHp902O3WKabBZN9s3noT4qifQ3SDmvXehWii9mCT4v-c_jcVaa-r</recordid><startdate>20100501</startdate><enddate>20100501</enddate><creator>Zhao, Carolyn Y.</creator><creator>Grinkevich, Vera</creator><creator>Nikulenkov, Fedor</creator><creator>Bao, Wenjie</creator><creator>Selivanova, Galina</creator><general>Taylor & Francis</general><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>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>20100501</creationdate><title>Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA</title><author>Zhao, Carolyn Y. ; Grinkevich, Vera ; Nikulenkov, Fedor ; Bao, Wenjie ; Selivanova, Galina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c493t-33e5b61d388efd24f7f2c40f6b3f7b939807484b5c837f31755f0932dc05c1443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Apoptosis</topic><topic>Binding</topic><topic>Biology</topic><topic>Bioscience</topic><topic>Calcium</topic><topic>Cancer</topic><topic>Cell</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cycle</topic><topic>Furans - therapeutic use</topic><topic>Humans</topic><topic>Landes</topic><topic>Mutation</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - radiotherapy</topic><topic>Organogenesis</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Transcriptional Activation</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Carolyn Y.</creatorcontrib><creatorcontrib>Grinkevich, Vera</creatorcontrib><creatorcontrib>Nikulenkov, Fedor</creatorcontrib><creatorcontrib>Bao, Wenjie</creatorcontrib><creatorcontrib>Selivanova, Galina</creatorcontrib><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>SwePub</collection><collection>SwePub Articles</collection><jtitle>Cell cycle (Georgetown, Tex.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Carolyn Y.</au><au>Grinkevich, Vera</au><au>Nikulenkov, Fedor</au><au>Bao, Wenjie</au><au>Selivanova, Galina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA</atitle><jtitle>Cell cycle (Georgetown, Tex.)</jtitle><addtitle>Cell Cycle</addtitle><date>2010-05-01</date><risdate>2010</risdate><volume>9</volume><issue>9</issue><spage>1847</spage><epage>1855</epage><pages>1847-1855</pages><issn>1538-4101</issn><eissn>1551-4005</eissn><abstract>Expression of mutant p53 correlates with poor prognosis in many tumors, therefore strategies aimed at reactivation of mutant p53 are likely to provide important benefits for treatment of tumors that are resistant to chemotherapy and radiotherapy. We have previously identified and characterized a small molecule RITA that binds p53 and induces a conformational change which prevents the binding to p53 of several inhibitors, including its own destructor MDM2. In this way, RITA rescues the tumor suppression function of wild type p53. Here, we demonstrate that RITA suppressed the growth and induced apoptosis in human tumor cell lines of a diverse origin carrying mutant p53 proteins. RITA restored transcriptional transactivation and transrepression function of several hot spot p53 mutants. The ability of RITA to rescue the activity of different p53 mutants suggests the generic mechanism of action. 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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Apoptosis Binding Biology Bioscience Calcium Cancer Cell Cell Line, Tumor Cell Proliferation Cycle Furans - therapeutic use Humans Landes Mutation Neoplasms - drug therapy Neoplasms - radiotherapy Organogenesis Protein Binding Proteins Proto-Oncogene Proteins c-mdm2 - metabolism Transcriptional Activation Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA |
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