A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation
Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with env...
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| Veröffentlicht in: | PLoS genetics 2014-10, Vol.10 (10), p.e1004721 |
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| creator | Esteve-Puig, Rosaura Gil, Rosa González-Sánchez, Elena Bech-Serra, Joan Josep Grueso, Judit Hernández-Losa, Javier Moliné, Teresa Canals, Francesc Ferrer, Berta Cortés, Javier Bastian, Boris Ramón Y Cajal, Santiago Martín-Caballero, Juan Flores, Juana Maria Vivancos, Ana García-Patos, Vicenç Recio, Juan Ángel |
| description | Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response. |
| doi_str_mv | 10.1371/journal.pgen.1004721 |
| format | Article |
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The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1004721</identifier><identifier>PMID: 25329316</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Animals, Newborn ; Apoptosis - genetics ; Apoptosis - radiation effects ; Biology and life sciences ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Disease Models, Animal ; DNA damage ; DNA Damage - radiation effects ; DNA repair ; Enzyme inhibitors ; Genetic aspects ; Genetic research ; Hepatocyte Growth Factor - genetics ; Humans ; Keratinocytes - metabolism ; Keratinocytes - pathology ; Keratinocytes - radiation effects ; Kinases ; Medicine and Health Sciences ; Mice, Transgenic ; Mutation ; Neoplasms, Squamous Cell - etiology ; Neoplasms, Squamous Cell - pathology ; Phosphorylation ; Protein Kinases - metabolism ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Proteolysis ; Repressor Proteins - metabolism ; Skin cancer ; Skin Neoplasms - etiology ; Skin Neoplasms - genetics ; Skin Neoplasms - pathology ; Ultraviolet radiation ; Ultraviolet Rays - adverse effects</subject><ispartof>PLoS genetics, 2014-10, Vol.10 (10), p.e1004721</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Esteve-Puig et al 2014 Esteve-Puig et al</rights><rights>2014 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: ) Degradation. PLoS Genet 10(10): e1004721. doi:10.1371/journal.pgen.1004721</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c768t-c46fb0e15b8b117ca39450ec3609b2901fb632b132e71b2b9638ae746f9909283</citedby><cites>FETCH-LOGICAL-c768t-c46fb0e15b8b117ca39450ec3609b2901fb632b132e71b2b9638ae746f9909283</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/PMC4199501/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199501/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25329316$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Esteve-Puig, Rosaura</creatorcontrib><creatorcontrib>Gil, Rosa</creatorcontrib><creatorcontrib>González-Sánchez, Elena</creatorcontrib><creatorcontrib>Bech-Serra, Joan Josep</creatorcontrib><creatorcontrib>Grueso, Judit</creatorcontrib><creatorcontrib>Hernández-Losa, Javier</creatorcontrib><creatorcontrib>Moliné, Teresa</creatorcontrib><creatorcontrib>Canals, Francesc</creatorcontrib><creatorcontrib>Ferrer, Berta</creatorcontrib><creatorcontrib>Cortés, Javier</creatorcontrib><creatorcontrib>Bastian, Boris</creatorcontrib><creatorcontrib>Ramón Y Cajal, Santiago</creatorcontrib><creatorcontrib>Martín-Caballero, Juan</creatorcontrib><creatorcontrib>Flores, Juana Maria</creatorcontrib><creatorcontrib>Vivancos, Ana</creatorcontrib><creatorcontrib>García-Patos, Vicenç</creatorcontrib><creatorcontrib>Recio, Juan Ángel</creatorcontrib><title>A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation</title><title>PLoS genetics</title><addtitle>PLoS Genet</addtitle><description>Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.</description><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Apoptosis - genetics</subject><subject>Apoptosis - radiation effects</subject><subject>Biology and life sciences</subject><subject>Cells, Cultured</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Disease Models, Animal</subject><subject>DNA damage</subject><subject>DNA Damage - radiation effects</subject><subject>DNA repair</subject><subject>Enzyme inhibitors</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Hepatocyte Growth Factor - genetics</subject><subject>Humans</subject><subject>Keratinocytes - metabolism</subject><subject>Keratinocytes - pathology</subject><subject>Keratinocytes - radiation effects</subject><subject>Kinases</subject><subject>Medicine and Health Sciences</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>Neoplasms, Squamous Cell - etiology</subject><subject>Neoplasms, Squamous Cell - pathology</subject><subject>Phosphorylation</subject><subject>Protein Kinases - metabolism</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proteolysis</subject><subject>Repressor Proteins - metabolism</subject><subject>Skin cancer</subject><subject>Skin Neoplasms - etiology</subject><subject>Skin Neoplasms - genetics</subject><subject>Skin Neoplasms - pathology</subject><subject>Ultraviolet radiation</subject><subject>Ultraviolet Rays - adverse effects</subject><issn>1553-7404</issn><issn>1553-7390</issn><issn>1553-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVkl9v0zAUxSMEYmPwDRBYQkLsoZ1vnMTxC1LWMahWdQjYeLT8L2lKYldxMsG3x6Xd1Eg8gCzZ1vXvnCtdnyh6CXgKhMLZ2g2dFc10Uxk7BYwTGsOj6BjSlExogpPHB_ej6Jn3a4xJmjP6NDqKUxIzAtlx9KNArRu8Cbs2DRqscnem82hxdQ5IeCQsurk9n9RWD8podLEskBatqAzyxnrXodboWvS1rdDs4moJBXq3ieF7cQlns_lnOEXaVJ3QgXD2efSkFI03L_bnSXRz-eHb7NNkcf1xPisWE0WzvJ-oJCslNpDKXAJQJQhLUmwUyTCTMcNQyozEEkhsKMhYsozkwtCgYgyzOCcn0eud76Zxnu_n5DlkeQoxYzEOxHxHaCfWfNPVreh-cSdq_qfguoqLrq9VY7gikkqZaJyWkBCRMUmpNlQZRUtN0q3X-323QYZhKGP7TjQj0_GLrVe8cnc8AcZSDMHgzc6gEqFfbUsXMNXWXvGC5CzHmGISqOlfqLC0aWvlrCnrUB8JTkeCwPTmZ1-JwXs-__rlP9jlv7PXt2P27QG7MqLpV941wzYNfgwmO1B1zvvOlA_zA8y3cb__Rr6NO9_HPcheHc7-QXSfb_IbpdL2UA</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Esteve-Puig, Rosaura</creator><creator>Gil, Rosa</creator><creator>González-Sánchez, Elena</creator><creator>Bech-Serra, Joan Josep</creator><creator>Grueso, Judit</creator><creator>Hernández-Losa, Javier</creator><creator>Moliné, Teresa</creator><creator>Canals, Francesc</creator><creator>Ferrer, Berta</creator><creator>Cortés, Javier</creator><creator>Bastian, Boris</creator><creator>Ramón Y Cajal, Santiago</creator><creator>Martín-Caballero, Juan</creator><creator>Flores, Juana Maria</creator><creator>Vivancos, Ana</creator><creator>García-Patos, Vicenç</creator><creator>Recio, Juan Ángel</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141001</creationdate><title>A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation</title><author>Esteve-Puig, Rosaura ; Gil, Rosa ; González-Sánchez, Elena ; Bech-Serra, Joan Josep ; Grueso, Judit ; Hernández-Losa, Javier ; Moliné, Teresa ; Canals, Francesc ; Ferrer, Berta ; Cortés, Javier ; Bastian, Boris ; Ramón Y Cajal, Santiago ; Martín-Caballero, Juan ; Flores, Juana Maria ; Vivancos, Ana ; García-Patos, Vicenç ; Recio, Juan Ángel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c768t-c46fb0e15b8b117ca39450ec3609b2901fb632b132e71b2b9638ae746f9909283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Apoptosis - genetics</topic><topic>Apoptosis - radiation effects</topic><topic>Biology and life sciences</topic><topic>Cells, Cultured</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Disease Models, Animal</topic><topic>DNA damage</topic><topic>DNA Damage - radiation effects</topic><topic>DNA repair</topic><topic>Enzyme inhibitors</topic><topic>Genetic aspects</topic><topic>Genetic research</topic><topic>Hepatocyte Growth Factor - genetics</topic><topic>Humans</topic><topic>Keratinocytes - metabolism</topic><topic>Keratinocytes - pathology</topic><topic>Keratinocytes - radiation effects</topic><topic>Kinases</topic><topic>Medicine and Health Sciences</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>Neoplasms, Squamous Cell - etiology</topic><topic>Neoplasms, Squamous Cell - pathology</topic><topic>Phosphorylation</topic><topic>Protein Kinases - metabolism</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proteolysis</topic><topic>Repressor Proteins - metabolism</topic><topic>Skin cancer</topic><topic>Skin Neoplasms - etiology</topic><topic>Skin Neoplasms - genetics</topic><topic>Skin Neoplasms - pathology</topic><topic>Ultraviolet radiation</topic><topic>Ultraviolet Rays - adverse effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Esteve-Puig, Rosaura</creatorcontrib><creatorcontrib>Gil, Rosa</creatorcontrib><creatorcontrib>González-Sánchez, Elena</creatorcontrib><creatorcontrib>Bech-Serra, Joan Josep</creatorcontrib><creatorcontrib>Grueso, Judit</creatorcontrib><creatorcontrib>Hernández-Losa, Javier</creatorcontrib><creatorcontrib>Moliné, Teresa</creatorcontrib><creatorcontrib>Canals, Francesc</creatorcontrib><creatorcontrib>Ferrer, Berta</creatorcontrib><creatorcontrib>Cortés, Javier</creatorcontrib><creatorcontrib>Bastian, Boris</creatorcontrib><creatorcontrib>Ramón Y Cajal, Santiago</creatorcontrib><creatorcontrib>Martín-Caballero, Juan</creatorcontrib><creatorcontrib>Flores, Juana Maria</creatorcontrib><creatorcontrib>Vivancos, Ana</creatorcontrib><creatorcontrib>García-Patos, Vicenç</creatorcontrib><creatorcontrib>Recio, Juan Ángel</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Esteve-Puig, Rosaura</au><au>Gil, Rosa</au><au>González-Sánchez, Elena</au><au>Bech-Serra, Joan Josep</au><au>Grueso, Judit</au><au>Hernández-Losa, Javier</au><au>Moliné, Teresa</au><au>Canals, Francesc</au><au>Ferrer, Berta</au><au>Cortés, Javier</au><au>Bastian, Boris</au><au>Ramón Y Cajal, Santiago</au><au>Martín-Caballero, Juan</au><au>Flores, Juana Maria</au><au>Vivancos, Ana</au><au>García-Patos, Vicenç</au><au>Recio, Juan Ángel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation</atitle><jtitle>PLoS genetics</jtitle><addtitle>PLoS Genet</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>10</volume><issue>10</issue><spage>e1004721</spage><pages>e1004721-</pages><issn>1553-7404</issn><issn>1553-7390</issn><eissn>1553-7404</eissn><abstract>Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25329316</pmid><doi>10.1371/journal.pgen.1004721</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Animals, Newborn Apoptosis - genetics Apoptosis - radiation effects Biology and life sciences Cells, Cultured Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Disease Models, Animal DNA damage DNA Damage - radiation effects DNA repair Enzyme inhibitors Genetic aspects Genetic research Hepatocyte Growth Factor - genetics Humans Keratinocytes - metabolism Keratinocytes - pathology Keratinocytes - radiation effects Kinases Medicine and Health Sciences Mice, Transgenic Mutation Neoplasms, Squamous Cell - etiology Neoplasms, Squamous Cell - pathology Phosphorylation Protein Kinases - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Proteolysis Repressor Proteins - metabolism Skin cancer Skin Neoplasms - etiology Skin Neoplasms - genetics Skin Neoplasms - pathology Ultraviolet radiation Ultraviolet Rays - adverse effects |
| title | A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation |
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