Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia
KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible anti...
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| Veröffentlicht in: | Toxicological sciences 2013-03, Vol.132 (1), p.151-161 |
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| creator | Saito, Kosuke Moore, Rick Negishi, Masahiko |
| description | KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice. |
| doi_str_mv | 10.1093/toxsci/kfs338 |
| format | Article |
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Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.</description><identifier>ISSN: 1096-6080</identifier><identifier>EISSN: 1096-0929</identifier><identifier>DOI: 10.1093/toxsci/kfs338</identifier><identifier>PMID: 23291559</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Amino Acid Sequence ; Animals ; Base Sequence ; Chromatin Immunoprecipitation ; DNA Primers ; Female ; Hyperplasia - chemically induced ; Hyperplasia - genetics ; Liver - drug effects ; Liver - metabolism ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Molecular Sequence Data ; Phenobarbital - toxicity ; Potassium Channels, Tandem Pore Domain - genetics ; Promoter Regions, Genetic ; Real-Time Polymerase Chain Reaction ; Receptors, Cytoplasmic and Nuclear - physiology</subject><ispartof>Toxicological sciences, 2013-03, Vol.132 (1), p.151-161</ispartof><rights>Published by Oxford University Press 2013. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-d36a79cc55e79e45f034be75bf52ca12d2407793848bcdae40a9e35bfe21d8c43</citedby><cites>FETCH-LOGICAL-c387t-d36a79cc55e79e45f034be75bf52ca12d2407793848bcdae40a9e35bfe21d8c43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23291559$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saito, Kosuke</creatorcontrib><creatorcontrib>Moore, Rick</creatorcontrib><creatorcontrib>Negishi, Masahiko</creatorcontrib><title>Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia</title><title>Toxicological sciences</title><addtitle>Toxicol Sci</addtitle><description>KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Chromatin Immunoprecipitation</subject><subject>DNA Primers</subject><subject>Female</subject><subject>Hyperplasia - chemically induced</subject><subject>Hyperplasia - genetics</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Sequence Data</subject><subject>Phenobarbital - toxicity</subject><subject>Potassium Channels, Tandem Pore Domain - genetics</subject><subject>Promoter Regions, Genetic</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Receptors, Cytoplasmic and Nuclear - physiology</subject><issn>1096-6080</issn><issn>1096-0929</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1vFDEMhkcIREvhyBX5DkOTyXzlglSt-FIrkBCcRx6PpxOaTaIks2V_DX-VhS0VnGz5tR8fnqJ4LsVrKbQ6z_5HInN-Myel-gfF6WHYlkJX-uFd34penBRPUvouhJSt0I-Lk0pVWjaNPi1-flrJMkaITByyj7C5-AIpMJnZEFq7B6Rsdpg5QV4Y8q0vg48Mly-BFnSOLVySu5FwzY7BONiiZdj6NTFYs-OYXsHtYmgBzJnd-ocUFnZ-xDiajLY0blqJJ1g4YDYEyz5wDBaTwafFoxlt4md39az49u7t182H8urz-4-bi6uSVN_lclItdpqoabjTXDezUPXIXTPOTUUoq6mqRddp1df9SBNyLVCzOsRcyamnWp0Vb47csI5bnohdjmiHEM0W437waIb_E2eW4drvBtV0rZDiACiPAIo-pcjz_a0Uw29Tw9HUcDR12H_x78P77b9q1C9K05cj</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Saito, Kosuke</creator><creator>Moore, Rick</creator><creator>Negishi, Masahiko</creator><general>Oxford University Press</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>5PM</scope></search><sort><creationdate>20130301</creationdate><title>Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia</title><author>Saito, Kosuke ; Moore, Rick ; Negishi, Masahiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-d36a79cc55e79e45f034be75bf52ca12d2407793848bcdae40a9e35bfe21d8c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Chromatin Immunoprecipitation</topic><topic>DNA Primers</topic><topic>Female</topic><topic>Hyperplasia - chemically induced</topic><topic>Hyperplasia - genetics</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C3H</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Sequence Data</topic><topic>Phenobarbital - toxicity</topic><topic>Potassium Channels, Tandem Pore Domain - genetics</topic><topic>Promoter Regions, Genetic</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Receptors, Cytoplasmic and Nuclear - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Saito, Kosuke</creatorcontrib><creatorcontrib>Moore, Rick</creatorcontrib><creatorcontrib>Negishi, Masahiko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Toxicological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Saito, Kosuke</au><au>Moore, Rick</au><au>Negishi, Masahiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia</atitle><jtitle>Toxicological sciences</jtitle><addtitle>Toxicol Sci</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>132</volume><issue>1</issue><spage>151</spage><epage>161</epage><pages>151-161</pages><issn>1096-6080</issn><eissn>1096-0929</eissn><abstract>KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>23291559</pmid><doi>10.1093/toxsci/kfs338</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Toxicological sciences, 2013-03, Vol.132 (1), p.151-161 |
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| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Animals Base Sequence Chromatin Immunoprecipitation DNA Primers Female Hyperplasia - chemically induced Hyperplasia - genetics Liver - drug effects Liver - metabolism Male Mice Mice, Inbred C3H Mice, Inbred C57BL Molecular Sequence Data Phenobarbital - toxicity Potassium Channels, Tandem Pore Domain - genetics Promoter Regions, Genetic Real-Time Polymerase Chain Reaction Receptors, Cytoplasmic and Nuclear - physiology |
| title | Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia |
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