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Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside / Gareth Jenkins; Shareen Doak; Katja Bruesehafer

Toxicological Sciences, Volume: 140, Issue: 1, Pages: 94 - 102

Swansea University Authors: Gareth, Jenkins, Shareen, Doak, Katja, Bruesehafer

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DOI (Published version): 10.1093/toxsci/kfu058

Abstract

The p53 tumor suppressor protein plays an essential role in cellularintegrity and inactivation of the TP53 gene by mutation isthe most frequent alteration in human cancer. As loss of p53 functionis associated with increased genetic instability, it is importantin genotoxicity testing to explore the r...

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Published in: Toxicological Sciences
Published: 2014
URI: https://cronfa.swan.ac.uk/Record/cronfa18150
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first_indexed 2014-07-22T01:30:21Z
last_indexed 2019-06-21T19:27:35Z
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2019-06-21T15:03:39.9629446</datestamp><bib-version>v2</bib-version><id>18150</id><entry>2014-07-21</entry><title>Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside</title><swanseaauthors><author><sid>a44095d26187304e903da7ca778697b6</sid><ORCID>0000-0002-5437-8389</ORCID><firstname>Gareth</firstname><surname>Jenkins</surname><name>Gareth Jenkins</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>8f70286908f67238a527a98cbf66d387</sid><ORCID>0000-0002-6753-1987</ORCID><firstname>Shareen</firstname><surname>Doak</surname><name>Shareen Doak</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>4362be1f5c0cd447b9d775355b145b07</sid><firstname>Katja</firstname><surname>Bruesehafer</surname><name>Katja Bruesehafer</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2014-07-21</date><deptcode>BMS</deptcode><abstract>The p53 tumor suppressor protein plays an essential role in cellularintegrity and inactivation of the TP53 gene by mutation isthe most frequent alteration in human cancer. As loss of p53 functionis associated with increased genetic instability, it is importantin genotoxicity testing to explore the role of p53 competency. Invitro model systems for genotoxicity testing are sometimes prone tomisleading positive results; some of this loss of predictivity may becaused by p53 inactivation in some cellmodels. To explore whetherimpaired p53 function plays a role in mutation sensitivity, TK6cells (p53 competent) and NH32 cells (p53 deficient) were treatedwith two known genotoxicants, mitomycin C (MMC) and cytosinearabinoside (araC). Chromosomal damage was assessed in the lowdose region by an automatedmicronucleus system and p53 activitywas investigated by gene and protein expression analysis. Cell cycleprogression studies were also assessed. Low levels of micronucleusand p53 induction were observed in TK6 cells treated with MMC.On the other hand, higher levels of micronucleus and p53 inductionwere shown in TK6 cells treated with araC and a G1/S arrestwas observed after araC treatment. p53 deficient NH32 cellsshowed an increased sensitivity of micronucleus (MN) inductionafter araC treatment compared with TK6 cells and less of an activeG1/S phase checkpoint. Thus, impaired p53 function sensitizescells to genotoxicants and plays a central role in the DNA damageresponse. This data has clear importance for safety assessment ofgenotoxicity and shows how crucial p53 competence.</abstract><type>Journal Article</type><journal>Toxicological Sciences</journal><volume>140</volume><journalNumber>1</journalNumber><paginationStart>94</paginationStart><paginationEnd>102</paginationEnd><publisher/><keywords>p53; genomic instability; cell cycle; micronucleus;</keywords><publishedDay>31</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2014</publishedYear><publishedDate>2014-07-31</publishedDate><doi>10.1093/toxsci/kfu058</doi><url/><notes></notes><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2019-06-21T15:03:39.9629446</lastEdited><Created>2014-07-21T11:02:02.3251831</Created><path><level id="1">Swansea University Medical School</level><level id="2">Medicine</level></path><authors><author><firstname>Gareth</firstname><surname>Jenkins</surname><orcid>0000-0002-5437-8389</orcid><order>1</order></author><author><firstname>Shareen</firstname><surname>Doak</surname><orcid>0000-0002-6753-1987</orcid><order>2</order></author><author><firstname>Katja</firstname><surname>Bruesehafer</surname><order>3</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2019-06-21T15:03:39.9629446 v2 18150 2014-07-21 Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside a44095d26187304e903da7ca778697b6 0000-0002-5437-8389 Gareth Jenkins Gareth Jenkins true false 8f70286908f67238a527a98cbf66d387 0000-0002-6753-1987 Shareen Doak Shareen Doak true false 4362be1f5c0cd447b9d775355b145b07 Katja Bruesehafer Katja Bruesehafer true false 2014-07-21 BMS The p53 tumor suppressor protein plays an essential role in cellularintegrity and inactivation of the TP53 gene by mutation isthe most frequent alteration in human cancer. As loss of p53 functionis associated with increased genetic instability, it is importantin genotoxicity testing to explore the role of p53 competency. Invitro model systems for genotoxicity testing are sometimes prone tomisleading positive results; some of this loss of predictivity may becaused by p53 inactivation in some cellmodels. To explore whetherimpaired p53 function plays a role in mutation sensitivity, TK6cells (p53 competent) and NH32 cells (p53 deficient) were treatedwith two known genotoxicants, mitomycin C (MMC) and cytosinearabinoside (araC). Chromosomal damage was assessed in the lowdose region by an automatedmicronucleus system and p53 activitywas investigated by gene and protein expression analysis. Cell cycleprogression studies were also assessed. Low levels of micronucleusand p53 induction were observed in TK6 cells treated with MMC.On the other hand, higher levels of micronucleus and p53 inductionwere shown in TK6 cells treated with araC and a G1/S arrestwas observed after araC treatment. p53 deficient NH32 cellsshowed an increased sensitivity of micronucleus (MN) inductionafter araC treatment compared with TK6 cells and less of an activeG1/S phase checkpoint. Thus, impaired p53 function sensitizescells to genotoxicants and plays a central role in the DNA damageresponse. This data has clear importance for safety assessment ofgenotoxicity and shows how crucial p53 competence. Journal Article Toxicological Sciences 140 1 94 102 p53; genomic instability; cell cycle; micronucleus; 31 7 2014 2014-07-31 10.1093/toxsci/kfu058 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-06-21T15:03:39.9629446 2014-07-21T11:02:02.3251831 Swansea University Medical School Medicine Gareth Jenkins 0000-0002-5437-8389 1 Shareen Doak 0000-0002-6753-1987 2 Katja Bruesehafer 3
title Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside
spellingShingle Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside
Gareth, Jenkins
Shareen, Doak
Katja, Bruesehafer
title_short Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside
title_full Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside
title_fullStr Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside
title_full_unstemmed Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside
title_sort Chromosome Breakage Induced by the Genotoxic Agents Mitomycin C and Cytosine arabinoside
author_id_str_mv a44095d26187304e903da7ca778697b6
8f70286908f67238a527a98cbf66d387
4362be1f5c0cd447b9d775355b145b07
author_id_fullname_str_mv a44095d26187304e903da7ca778697b6_***_Gareth, Jenkins
8f70286908f67238a527a98cbf66d387_***_Shareen, Doak
4362be1f5c0cd447b9d775355b145b07_***_Katja, Bruesehafer
author Gareth, Jenkins
Shareen, Doak
Katja, Bruesehafer
author2 Gareth Jenkins
Shareen Doak
Katja Bruesehafer
format Journal article
container_title Toxicological Sciences
container_volume 140
container_issue 1
container_start_page 94
publishDate 2014
institution Swansea University
doi_str_mv 10.1093/toxsci/kfu058
college_str Swansea University Medical School
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hierarchy_top_id swanseauniversitymedicalschool
hierarchy_top_title Swansea University Medical School
hierarchy_parent_id swanseauniversitymedicalschool
hierarchy_parent_title Swansea University Medical School
department_str Medicine{{{_:::_}}}Swansea University Medical School{{{_:::_}}}Medicine
document_store_str 0
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description The p53 tumor suppressor protein plays an essential role in cellularintegrity and inactivation of the TP53 gene by mutation isthe most frequent alteration in human cancer. As loss of p53 functionis associated with increased genetic instability, it is importantin genotoxicity testing to explore the role of p53 competency. Invitro model systems for genotoxicity testing are sometimes prone tomisleading positive results; some of this loss of predictivity may becaused by p53 inactivation in some cellmodels. To explore whetherimpaired p53 function plays a role in mutation sensitivity, TK6cells (p53 competent) and NH32 cells (p53 deficient) were treatedwith two known genotoxicants, mitomycin C (MMC) and cytosinearabinoside (araC). Chromosomal damage was assessed in the lowdose region by an automatedmicronucleus system and p53 activitywas investigated by gene and protein expression analysis. Cell cycleprogression studies were also assessed. Low levels of micronucleusand p53 induction were observed in TK6 cells treated with MMC.On the other hand, higher levels of micronucleus and p53 inductionwere shown in TK6 cells treated with araC and a G1/S arrestwas observed after araC treatment. p53 deficient NH32 cellsshowed an increased sensitivity of micronucleus (MN) inductionafter araC treatment compared with TK6 cells and less of an activeG1/S phase checkpoint. Thus, impaired p53 function sensitizescells to genotoxicants and plays a central role in the DNA damageresponse. This data has clear importance for safety assessment ofgenotoxicity and shows how crucial p53 competence.
published_date 2014-07-31T03:31:18Z
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