The transcription factor p53: Not a repressor, solely an activator
The predominant function of the tumor suppressor p53 is transcriptional regulation. It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional rep...
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| Veröffentlicht in: | Cell cycle (Georgetown, Tex.) Tex.), 2014-10, Vol.13 (19), p.3037-3058 |
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| creator | Fischer, Martin Steiner, Lydia Engeland, Kurt |
| description | The predominant function of the tumor suppressor p53 is transcriptional regulation. It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. As an alternative to models of direct repression, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21-DREAM/RB pathway. |
| doi_str_mv | 10.4161/15384101.2014.949083 |
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It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. As an alternative to models of direct repression, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21-DREAM/RB pathway.</description><identifier>ISSN: 1538-4101</identifier><identifier>ISSN: 1551-4005</identifier><identifier>EISSN: 1551-4005</identifier><identifier>DOI: 10.4161/15384101.2014.949083</identifier><identifier>PMID: 25486564</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Binding Sites ; CDKN1A ; Chromatin Immunoprecipitation ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; DREAM complex ; E2F Transcription Factors - chemistry ; E2F Transcription Factors - genetics ; E2F Transcription Factors - metabolism ; E2F/RB complex ; genome-wide meta-analysis ; HCT116 Cells ; Humans ; Meta-Analysis as Topic ; Promoter Regions, Genetic ; Protein Binding ; Real-Time Polymerase Chain Reaction ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Retinoblastoma Protein - genetics ; Retinoblastoma Protein - metabolism ; RNA, Messenger - metabolism ; RNA, Untranslated - metabolism ; Signal Transduction ; Transcriptional Activation ; Tumor Suppressor Protein p53 - chemistry ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Cell cycle (Georgetown, Tex.), 2014-10, Vol.13 (19), p.3037-3058</ispartof><rights>2014 The Author(s). Published with license by Taylor & Francis Group, LLC © Martin Fischer, Lydia Steiner, and Kurt Engeland 2014</rights><rights>2014 The Author(s). 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It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. As an alternative to models of direct repression, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21-DREAM/RB pathway.</description><subject>Binding Sites</subject><subject>CDKN1A</subject><subject>Chromatin Immunoprecipitation</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>DREAM complex</subject><subject>E2F Transcription Factors - chemistry</subject><subject>E2F Transcription Factors - genetics</subject><subject>E2F Transcription Factors - metabolism</subject><subject>E2F/RB complex</subject><subject>genome-wide meta-analysis</subject><subject>HCT116 Cells</subject><subject>Humans</subject><subject>Meta-Analysis as Topic</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Binding</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Retinoblastoma Protein - genetics</subject><subject>Retinoblastoma Protein - metabolism</subject><subject>RNA, Messenger - metabolism</subject><subject>RNA, Untranslated - metabolism</subject><subject>Signal Transduction</subject><subject>Transcriptional Activation</subject><subject>Tumor Suppressor Protein p53 - chemistry</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>1538-4101</issn><issn>1551-4005</issn><issn>1551-4005</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc1OwzAQhC0EoqXwBgj5yIEUO7bThAMIKv6kCi69W66zoUZJHOy0qG-Po7QVXDjtSvvt7HiM0DklY04Tek0FSzkldBwTyscZz0jKDtCQCkEjTog47HqWRh0zQCfefxISp5OMHqNBLHiaiIQP0cN8Cbh1qvbamaY1tsaF0q11uBHsBr_ZFivsoHHgvXVX2NsSyg1WNQ6UWatAnqKjQpUezrZ1hOZPj_PpSzR7f36d3s8izRPeRjroTgRJ0wyIXnDCdAahBN8xCMoyAWmhGF2A1hlNIJ9oCA8TLFeC6yJmI3TbyzarRQW5hjrYLmXjTKXcRlpl5N9JbZbyw64lT2jMRSdwuRVw9msFvpWV8RrKUtVgV17ShAlCWEySgPIe1c5676DYn6FEdunLXfqyS1_26Ye1i98W90u7uANw1wOmLqyr1Ld1ZS5btSmtK8InaOMl-_fED8F3lEc</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Fischer, Martin</creator><creator>Steiner, Lydia</creator><creator>Engeland, Kurt</creator><general>Taylor & Francis</general><scope>0YH</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>20141001</creationdate><title>The transcription factor p53: Not a repressor, solely an activator</title><author>Fischer, Martin ; Steiner, Lydia ; Engeland, Kurt</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c464t-cfac750889e0cb403c9eb404902e51395e8fa31becc916ed7ce01453da54cf23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Binding Sites</topic><topic>CDKN1A</topic><topic>Chromatin Immunoprecipitation</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>DREAM complex</topic><topic>E2F Transcription Factors - chemistry</topic><topic>E2F Transcription Factors - genetics</topic><topic>E2F Transcription Factors - metabolism</topic><topic>E2F/RB complex</topic><topic>genome-wide meta-analysis</topic><topic>HCT116 Cells</topic><topic>Humans</topic><topic>Meta-Analysis as Topic</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Binding</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Retinoblastoma Protein - genetics</topic><topic>Retinoblastoma Protein - metabolism</topic><topic>RNA, Messenger - metabolism</topic><topic>RNA, Untranslated - metabolism</topic><topic>Signal Transduction</topic><topic>Transcriptional Activation</topic><topic>Tumor Suppressor Protein p53 - chemistry</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fischer, Martin</creatorcontrib><creatorcontrib>Steiner, Lydia</creatorcontrib><creatorcontrib>Engeland, Kurt</creatorcontrib><collection>Taylor & Francis 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>Cell cycle (Georgetown, Tex.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fischer, Martin</au><au>Steiner, Lydia</au><au>Engeland, Kurt</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The transcription factor p53: Not a repressor, solely an activator</atitle><jtitle>Cell cycle (Georgetown, Tex.)</jtitle><addtitle>Cell Cycle</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>13</volume><issue>19</issue><spage>3037</spage><epage>3058</epage><pages>3037-3058</pages><issn>1538-4101</issn><issn>1551-4005</issn><eissn>1551-4005</eissn><abstract>The predominant function of the tumor suppressor p53 is transcriptional regulation. It is generally accepted that p53-dependent transcriptional activation occurs by binding to a specific recognition site in promoters of target genes. Additionally, several models for p53-dependent transcriptional repression have been postulated. Here, we evaluate these models based on a computational meta-analysis of genome-wide data. Surprisingly, several major models of p53-dependent gene regulation are implausible. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and falsifies models of direct repression. This notion is supported by experimental re-analysis of representative genes reported as directly repressed by p53. Therefore, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors as well as models based on the function of ncRNAs are also not supported by the meta-analysis. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Binding Sites CDKN1A Chromatin Immunoprecipitation Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism DREAM complex E2F Transcription Factors - chemistry E2F Transcription Factors - genetics E2F Transcription Factors - metabolism E2F/RB complex genome-wide meta-analysis HCT116 Cells Humans Meta-Analysis as Topic Promoter Regions, Genetic Protein Binding Real-Time Polymerase Chain Reaction Repressor Proteins - genetics Repressor Proteins - metabolism Retinoblastoma Protein - genetics Retinoblastoma Protein - metabolism RNA, Messenger - metabolism RNA, Untranslated - metabolism Signal Transduction Transcriptional Activation Tumor Suppressor Protein p53 - chemistry Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | The transcription factor p53: Not a repressor, solely an activator |
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