ATP-dependent activation of p21WAF¹/CIP¹-associated Cdk2 by Cdc6
When cells progressing in mid-S phase are damaged with a base-modifying chemical, they arrest in S phase long after the CHK1 checkpoint signal fades out, partly because of p53-mediated long-lasting induction of the cyclin-dependent kinase inhibitor p21WAF¹/CIP¹. We have recently found that enforced...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2008-03, Vol.105 (12), p.4757-4762 |
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creator | Kan, Qiuming Jinno, Shigeki Yamamoto, Hanako Kobayashi, Kohei Okayama, Hiroto |
description | When cells progressing in mid-S phase are damaged with a base-modifying chemical, they arrest in S phase long after the CHK1 checkpoint signal fades out, partly because of p53-mediated long-lasting induction of the cyclin-dependent kinase inhibitor p21WAF¹/CIP¹. We have recently found that enforced expression of Cdc6, the assembler of prereplicative complexes, markedly advances recovery from the prolonged S-phase arrest and reactivation of Cdk2 despite the presence of a high level of induced p21. Here, we report that Cdc6 protein can activate p21-associated Cdk2 in an ATP-dependent manner in vitro. Consistently, Cdc6 mutated for ATPase or a putative cyclin binding motif is no longer able to activate the Cdk2 in vitro or promote reinitiation of S-phase progression and reactivation of Cdk2 in vivo. These results reveal the never anticipated function of Cdc6 and redefine its role in the control of S-phase progression in mammalian cells. |
doi_str_mv | 10.1073/pnas.0706392105 |
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We have recently found that enforced expression of Cdc6, the assembler of prereplicative complexes, markedly advances recovery from the prolonged S-phase arrest and reactivation of Cdk2 despite the presence of a high level of induced p21. Here, we report that Cdc6 protein can activate p21-associated Cdk2 in an ATP-dependent manner in vitro. Consistently, Cdc6 mutated for ATPase or a putative cyclin binding motif is no longer able to activate the Cdk2 in vitro or promote reinitiation of S-phase progression and reactivation of Cdk2 in vivo. These results reveal the never anticipated function of Cdc6 and redefine its role in the control of S-phase progression in mammalian cells.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0706392105</identifier><identifier>PMID: 18356301</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adenosine Triphosphatases - metabolism ; Adenosine Triphosphate - pharmacology ; Amino Acid Motifs ; Animals ; Biological Sciences ; Cell Cycle Proteins - chemistry ; Cell Cycle Proteins - metabolism ; Chromosomal Proteins, Non-Histone - chemistry ; Chromosomal Proteins, Non-Histone - metabolism ; Cyclin-Dependent Kinase 2 - metabolism ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Cyclin-Dependent Kinase Inhibitor p27 - metabolism ; Cyclins - metabolism ; Enzyme Activation - drug effects ; Methyl Methanesulfonate - pharmacology ; Mice ; Mutation - genetics ; Protein Binding - drug effects ; Rats ; S Phase - drug effects</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-03, Vol.105 (12), p.4757-4762</ispartof><rights>2008 by The National Academy of Sciences of the USA</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/12.cover.gif</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290776/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290776/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18356301$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kan, Qiuming</creatorcontrib><creatorcontrib>Jinno, Shigeki</creatorcontrib><creatorcontrib>Yamamoto, Hanako</creatorcontrib><creatorcontrib>Kobayashi, Kohei</creatorcontrib><creatorcontrib>Okayama, Hiroto</creatorcontrib><title>ATP-dependent activation of p21WAF¹/CIP¹-associated Cdk2 by Cdc6</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>When cells progressing in mid-S phase are damaged with a base-modifying chemical, they arrest in S phase long after the CHK1 checkpoint signal fades out, partly because of p53-mediated long-lasting induction of the cyclin-dependent kinase inhibitor p21WAF¹/CIP¹. We have recently found that enforced expression of Cdc6, the assembler of prereplicative complexes, markedly advances recovery from the prolonged S-phase arrest and reactivation of Cdk2 despite the presence of a high level of induced p21. Here, we report that Cdc6 protein can activate p21-associated Cdk2 in an ATP-dependent manner in vitro. Consistently, Cdc6 mutated for ATPase or a putative cyclin binding motif is no longer able to activate the Cdk2 in vitro or promote reinitiation of S-phase progression and reactivation of Cdk2 in vivo. 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Jinno, Shigeki ; Yamamoto, Hanako ; Kobayashi, Kohei ; Okayama, Hiroto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-f2566-963f2b09ede79e6d6cdc1328215090446fe4a3ff10bc797895584865623f62393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adenosine Triphosphatases - metabolism</topic><topic>Adenosine Triphosphate - pharmacology</topic><topic>Amino Acid Motifs</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>Cell Cycle Proteins - chemistry</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Chromosomal Proteins, Non-Histone - chemistry</topic><topic>Chromosomal Proteins, Non-Histone - metabolism</topic><topic>Cyclin-Dependent Kinase 2 - metabolism</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Cyclin-Dependent Kinase Inhibitor p27 - metabolism</topic><topic>Cyclins - metabolism</topic><topic>Enzyme Activation - drug effects</topic><topic>Methyl Methanesulfonate - pharmacology</topic><topic>Mice</topic><topic>Mutation - genetics</topic><topic>Protein Binding - drug effects</topic><topic>Rats</topic><topic>S Phase - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kan, Qiuming</creatorcontrib><creatorcontrib>Jinno, Shigeki</creatorcontrib><creatorcontrib>Yamamoto, Hanako</creatorcontrib><creatorcontrib>Kobayashi, Kohei</creatorcontrib><creatorcontrib>Okayama, Hiroto</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kan, Qiuming</au><au>Jinno, Shigeki</au><au>Yamamoto, Hanako</au><au>Kobayashi, Kohei</au><au>Okayama, Hiroto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>ATP-dependent activation of p21WAF¹/CIP¹-associated Cdk2 by Cdc6</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2008-03-25</date><risdate>2008</risdate><volume>105</volume><issue>12</issue><spage>4757</spage><epage>4762</epage><pages>4757-4762</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>When cells progressing in mid-S phase are damaged with a base-modifying chemical, they arrest in S phase long after the CHK1 checkpoint signal fades out, partly because of p53-mediated long-lasting induction of the cyclin-dependent kinase inhibitor p21WAF¹/CIP¹. We have recently found that enforced expression of Cdc6, the assembler of prereplicative complexes, markedly advances recovery from the prolonged S-phase arrest and reactivation of Cdk2 despite the presence of a high level of induced p21. Here, we report that Cdc6 protein can activate p21-associated Cdk2 in an ATP-dependent manner in vitro. Consistently, Cdc6 mutated for ATPase or a putative cyclin binding motif is no longer able to activate the Cdk2 in vitro or promote reinitiation of S-phase progression and reactivation of Cdk2 in vivo. These results reveal the never anticipated function of Cdc6 and redefine its role in the control of S-phase progression in mammalian cells.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>18356301</pmid><doi>10.1073/pnas.0706392105</doi><tpages>6</tpages></addata></record> |
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subjects | Adenosine Triphosphatases - metabolism Adenosine Triphosphate - pharmacology Amino Acid Motifs Animals Biological Sciences Cell Cycle Proteins - chemistry Cell Cycle Proteins - metabolism Chromosomal Proteins, Non-Histone - chemistry Chromosomal Proteins, Non-Histone - metabolism Cyclin-Dependent Kinase 2 - metabolism Cyclin-Dependent Kinase Inhibitor p21 - metabolism Cyclin-Dependent Kinase Inhibitor p27 - metabolism Cyclins - metabolism Enzyme Activation - drug effects Methyl Methanesulfonate - pharmacology Mice Mutation - genetics Protein Binding - drug effects Rats S Phase - drug effects |
title | ATP-dependent activation of p21WAF¹/CIP¹-associated Cdk2 by Cdc6 |
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