Chk2 mediates RITA-induced apoptosis
Reactivation of the p53 tumor-suppressor protein by small molecules like Nutlin-3 and RITA (reactivation of p53 and induction of tumor cell apoptosis) is a promising strategy for cancer therapy. The molecular mechanisms involved in the responses to RITA remain enigmatic. Several groups reported the...
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| Veröffentlicht in: | Cell death and differentiation 2012-06, Vol.19 (6), p.980-989 |
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| description | Reactivation of the p53 tumor-suppressor protein by small molecules like Nutlin-3 and RITA (reactivation of p53 and induction of tumor cell apoptosis) is a promising strategy for cancer therapy. The molecular mechanisms involved in the responses to RITA remain enigmatic. Several groups reported the induction of a p53-dependent DNA damage response. Furthermore, the existence of a p53-dependent S-phase checkpoint has been suggested, involving the checkpoint kinase Chk1. We have recently shown synergistic induction of apoptosis by RITA in combination with Nutlin-3, and we observed concomitant Chk2 phosphorylation. Therefore, we investigated whether Chk2 contributes to the cellular responses to RITA. Strikingly, the induction of apoptosis seemed entirely Chk2 dependent. Transcriptional activity of p53 in response to RITA required the presence of Chk2. A partial rescue of apoptosis observed in Noxa knockdown cells emphasized the relevance of p53 transcriptional activity for RITA-induced apoptosis. In addition, we observed an early p53- and Chk2-dependent block of DNA replication upon RITA treatment. Replicating cells seemed more prone to entering RITA-induced apoptosis. Furthermore, the RITA-induced DNA damage response, which was not a secondary effect of apoptosis induction, was strongly attenuated in cells lacking p53 or Chk2. In conclusion, we identified Chk2 as an essential mediator of the cellular responses to RITA. |
| doi_str_mv | 10.1038/cdd.2011.182 |
| format | Article |
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The molecular mechanisms involved in the responses to RITA remain enigmatic. Several groups reported the induction of a p53-dependent DNA damage response. Furthermore, the existence of a p53-dependent S-phase checkpoint has been suggested, involving the checkpoint kinase Chk1. We have recently shown synergistic induction of apoptosis by RITA in combination with Nutlin-3, and we observed concomitant Chk2 phosphorylation. Therefore, we investigated whether Chk2 contributes to the cellular responses to RITA. Strikingly, the induction of apoptosis seemed entirely Chk2 dependent. Transcriptional activity of p53 in response to RITA required the presence of Chk2. A partial rescue of apoptosis observed in Noxa knockdown cells emphasized the relevance of p53 transcriptional activity for RITA-induced apoptosis. In addition, we observed an early p53- and Chk2-dependent block of DNA replication upon RITA treatment. Replicating cells seemed more prone to entering RITA-induced apoptosis. Furthermore, the RITA-induced DNA damage response, which was not a secondary effect of apoptosis induction, was strongly attenuated in cells lacking p53 or Chk2. In conclusion, we identified Chk2 as an essential mediator of the cellular responses to RITA.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/cdd.2011.182</identifier><identifier>PMID: 22158418</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Apoptosis - drug effects ; Ataxia ; Biochemistry ; Biomedical and Life Sciences ; Cancer therapies ; Cell Biology ; Cell Cycle Analysis ; Cell death ; Cell Line, Tumor ; Checkpoint Kinase 2 ; DNA damage ; Furans - pharmacology ; G2 Phase Cell Cycle Checkpoints ; HCT116 Cells ; Humans ; Imidazoles - pharmacology ; Kinases ; Life Sciences ; Melanoma ; Original Paper ; Phosphatase ; Phosphorylation ; Piperazines - pharmacology ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; RNA Interference ; RNA, Small Interfering - metabolism ; Stem Cells ; Tumor Suppressor Protein p53 - antagonists & inhibitors ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors</subject><ispartof>Cell death and differentiation, 2012-06, Vol.19 (6), p.980-989</ispartof><rights>Macmillan Publishers Limited 2012</rights><rights>Copyright Nature Publishing Group Jun 2012</rights><rights>Copyright © 2012 Macmillan Publishers Limited 2012 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c450t-31c8fc9f05dc91b9fe6e03acf513d855268574d00d7821d46565fb855d8fbac93</citedby><cites>FETCH-LOGICAL-c450t-31c8fc9f05dc91b9fe6e03acf513d855268574d00d7821d46565fb855d8fbac93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354051/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3354051/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,41488,42557,51319,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22158418$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Lange, J</creatorcontrib><creatorcontrib>Verlaan-de Vries, M</creatorcontrib><creatorcontrib>Teunisse, A F A S</creatorcontrib><creatorcontrib>Jochemsen, A G</creatorcontrib><title>Chk2 mediates RITA-induced apoptosis</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>Reactivation of the p53 tumor-suppressor protein by small molecules like Nutlin-3 and RITA (reactivation of p53 and induction of tumor cell apoptosis) is a promising strategy for cancer therapy. The molecular mechanisms involved in the responses to RITA remain enigmatic. Several groups reported the induction of a p53-dependent DNA damage response. Furthermore, the existence of a p53-dependent S-phase checkpoint has been suggested, involving the checkpoint kinase Chk1. We have recently shown synergistic induction of apoptosis by RITA in combination with Nutlin-3, and we observed concomitant Chk2 phosphorylation. Therefore, we investigated whether Chk2 contributes to the cellular responses to RITA. Strikingly, the induction of apoptosis seemed entirely Chk2 dependent. Transcriptional activity of p53 in response to RITA required the presence of Chk2. A partial rescue of apoptosis observed in Noxa knockdown cells emphasized the relevance of p53 transcriptional activity for RITA-induced apoptosis. In addition, we observed an early p53- and Chk2-dependent block of DNA replication upon RITA treatment. Replicating cells seemed more prone to entering RITA-induced apoptosis. Furthermore, the RITA-induced DNA damage response, which was not a secondary effect of apoptosis induction, was strongly attenuated in cells lacking p53 or Chk2. In conclusion, we identified Chk2 as an essential mediator of the cellular responses to RITA.</description><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Ataxia</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cancer therapies</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Checkpoint Kinase 2</subject><subject>DNA damage</subject><subject>Furans - pharmacology</subject><subject>G2 Phase Cell Cycle Checkpoints</subject><subject>HCT116 Cells</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Melanoma</subject><subject>Original Paper</subject><subject>Phosphatase</subject><subject>Phosphorylation</subject><subject>Piperazines - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - 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drug effects</topic><topic>Ataxia</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cancer therapies</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Checkpoint Kinase 2</topic><topic>DNA damage</topic><topic>Furans - pharmacology</topic><topic>G2 Phase Cell Cycle Checkpoints</topic><topic>HCT116 Cells</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Melanoma</topic><topic>Original Paper</topic><topic>Phosphatase</topic><topic>Phosphorylation</topic><topic>Piperazines - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - metabolism</topic><topic>Stem Cells</topic><topic>Tumor Suppressor Protein p53 - antagonists & inhibitors</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>de Lange, J</creatorcontrib><creatorcontrib>Verlaan-de Vries, M</creatorcontrib><creatorcontrib>Teunisse, A F A S</creatorcontrib><creatorcontrib>Jochemsen, A G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>de Lange, J</au><au>Verlaan-de Vries, M</au><au>Teunisse, A F A S</au><au>Jochemsen, A G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chk2 mediates RITA-induced apoptosis</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2012-06-01</date><risdate>2012</risdate><volume>19</volume><issue>6</issue><spage>980</spage><epage>989</epage><pages>980-989</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>Reactivation of the p53 tumor-suppressor protein by small molecules like Nutlin-3 and RITA (reactivation of p53 and induction of tumor cell apoptosis) is a promising strategy for cancer therapy. The molecular mechanisms involved in the responses to RITA remain enigmatic. Several groups reported the induction of a p53-dependent DNA damage response. Furthermore, the existence of a p53-dependent S-phase checkpoint has been suggested, involving the checkpoint kinase Chk1. We have recently shown synergistic induction of apoptosis by RITA in combination with Nutlin-3, and we observed concomitant Chk2 phosphorylation. Therefore, we investigated whether Chk2 contributes to the cellular responses to RITA. Strikingly, the induction of apoptosis seemed entirely Chk2 dependent. Transcriptional activity of p53 in response to RITA required the presence of Chk2. A partial rescue of apoptosis observed in Noxa knockdown cells emphasized the relevance of p53 transcriptional activity for RITA-induced apoptosis. In addition, we observed an early p53- and Chk2-dependent block of DNA replication upon RITA treatment. Replicating cells seemed more prone to entering RITA-induced apoptosis. Furthermore, the RITA-induced DNA damage response, which was not a secondary effect of apoptosis induction, was strongly attenuated in cells lacking p53 or Chk2. In conclusion, we identified Chk2 as an essential mediator of the cellular responses to RITA.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22158418</pmid><doi>10.1038/cdd.2011.182</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Apoptosis Apoptosis - drug effects Ataxia Biochemistry Biomedical and Life Sciences Cancer therapies Cell Biology Cell Cycle Analysis Cell death Cell Line, Tumor Checkpoint Kinase 2 DNA damage Furans - pharmacology G2 Phase Cell Cycle Checkpoints HCT116 Cells Humans Imidazoles - pharmacology Kinases Life Sciences Melanoma Original Paper Phosphatase Phosphorylation Piperazines - pharmacology Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism RNA Interference RNA, Small Interfering - metabolism Stem Cells Tumor Suppressor Protein p53 - antagonists & inhibitors Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors |
| title | Chk2 mediates RITA-induced apoptosis |
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