Mutant p53 R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis

In human breast cancer, mutations in the p53 gene are associated with poor prognosis. However, analysis of patient data so far did not clarify, whether missense point mutations in the p53 gene, in addition to causing loss of wild‐type p53 function, also confer a gain of function phenotype to the enc...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:International journal of cancer 2008-04, Vol.122 (8), p.1701-1709
Hauptverfasser: Heinlein, Christina, Krepulat, Frauke, Löhler, Jürgen, Speidel, Daniel, Deppert, Wolfgang, Tolstonog, Genrich V.
Format: Artikel
Sprache:eng
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1709
container_issue 8
container_start_page 1701
container_title International journal of cancer
container_volume 122
creator Heinlein, Christina
Krepulat, Frauke
Löhler, Jürgen
Speidel, Daniel
Deppert, Wolfgang
Tolstonog, Genrich V.
description In human breast cancer, mutations in the p53 gene are associated with poor prognosis. However, analysis of patient data so far did not clarify, whether missense point mutations in the p53 gene, in addition to causing loss of wild‐type p53 function, also confer a gain of function phenotype to the encoded mutant p53. As heterogeneity of patient material and data might obscure a clear answer, we studied the effects of a coexpressed mutant p53 R270H in transgenic mice in which SV40 early proteins initiate the development of mammary adenocarcinoma (WAP‐T mice). In such tumors the endogenous wild‐type p53 is functionally compromised by complex formation with SV40 T‐antigen, thereby constituting a loss of wild‐type p53 function situation that allowed analysis of the postulated gain of function effects of mutant p53 R270H . We found that mutant p53 R270H in bi‐transgenic mice enhanced the transition from intraepithelial neoplasia to invasive carcinoma, resulting in a higher frequency of invasive carcinoma per gland and per mouse, a more severe tumor phenotype, and more frequent pulmonary metastasis. Surprisingly, mutant p53 R270H in this system does not increase genomic instability. Therefore, other postulated gain of function activities of mutant p53 must be responsible for the effects described here. © 2007 Wiley‐Liss, Inc.
doi_str_mv 10.1002/ijc.23317
format Article
fullrecord <record><control><sourceid>crossref</sourceid><recordid>TN_cdi_crossref_primary_10_1002_ijc_23317</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1002_ijc_23317</sourcerecordid><originalsourceid>FETCH-LOGICAL-c159t-6596c9da6ebbc60d9bbe88a167753368a35fb96aa0a85c06971ed771233d0ca73</originalsourceid><addsrcrecordid>eNotkLFOwzAURS0EEqEw8AdeGVKeY2zHI6qAIhUhIZijF9spjho7ipOhG5_AN_IlpIXl3eFIV_cdQq4ZLBlAcetbsyw4Z-qEZAy0yqFg4pRkM4NcMS7PyUVKLQBjAu4y0r5MI4aR9oLTt0LBmm7RBxob2kzBjD4G2n-6EMd97-gMkHZxSm6-1u1oEwcag4lbF9zP17cPdjLO0g67Doc9NTgYH440-XRJzhrcJXf1nwvy8fjwvlrnm9en59X9JjdM6DGXQkujLUpX10aC1XXtyhKZVEpwLkvkoqm1RAQshQGpFXNWKTZ_bcGg4gty89drhpjS4JqqH_xhT8WgOkiqZknVURL_BUYHW7I</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Mutant p53 R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis</title><source>Wiley Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Heinlein, Christina ; Krepulat, Frauke ; Löhler, Jürgen ; Speidel, Daniel ; Deppert, Wolfgang ; Tolstonog, Genrich V.</creator><creatorcontrib>Heinlein, Christina ; Krepulat, Frauke ; Löhler, Jürgen ; Speidel, Daniel ; Deppert, Wolfgang ; Tolstonog, Genrich V.</creatorcontrib><description>In human breast cancer, mutations in the p53 gene are associated with poor prognosis. However, analysis of patient data so far did not clarify, whether missense point mutations in the p53 gene, in addition to causing loss of wild‐type p53 function, also confer a gain of function phenotype to the encoded mutant p53. As heterogeneity of patient material and data might obscure a clear answer, we studied the effects of a coexpressed mutant p53 R270H in transgenic mice in which SV40 early proteins initiate the development of mammary adenocarcinoma (WAP‐T mice). In such tumors the endogenous wild‐type p53 is functionally compromised by complex formation with SV40 T‐antigen, thereby constituting a loss of wild‐type p53 function situation that allowed analysis of the postulated gain of function effects of mutant p53 R270H . We found that mutant p53 R270H in bi‐transgenic mice enhanced the transition from intraepithelial neoplasia to invasive carcinoma, resulting in a higher frequency of invasive carcinoma per gland and per mouse, a more severe tumor phenotype, and more frequent pulmonary metastasis. Surprisingly, mutant p53 R270H in this system does not increase genomic instability. Therefore, other postulated gain of function activities of mutant p53 must be responsible for the effects described here. © 2007 Wiley‐Liss, Inc.</description><identifier>ISSN: 0020-7136</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.23317</identifier><language>eng</language><ispartof>International journal of cancer, 2008-04, Vol.122 (8), p.1701-1709</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c159t-6596c9da6ebbc60d9bbe88a167753368a35fb96aa0a85c06971ed771233d0ca73</citedby><cites>FETCH-LOGICAL-c159t-6596c9da6ebbc60d9bbe88a167753368a35fb96aa0a85c06971ed771233d0ca73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Heinlein, Christina</creatorcontrib><creatorcontrib>Krepulat, Frauke</creatorcontrib><creatorcontrib>Löhler, Jürgen</creatorcontrib><creatorcontrib>Speidel, Daniel</creatorcontrib><creatorcontrib>Deppert, Wolfgang</creatorcontrib><creatorcontrib>Tolstonog, Genrich V.</creatorcontrib><title>Mutant p53 R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis</title><title>International journal of cancer</title><description>In human breast cancer, mutations in the p53 gene are associated with poor prognosis. However, analysis of patient data so far did not clarify, whether missense point mutations in the p53 gene, in addition to causing loss of wild‐type p53 function, also confer a gain of function phenotype to the encoded mutant p53. As heterogeneity of patient material and data might obscure a clear answer, we studied the effects of a coexpressed mutant p53 R270H in transgenic mice in which SV40 early proteins initiate the development of mammary adenocarcinoma (WAP‐T mice). In such tumors the endogenous wild‐type p53 is functionally compromised by complex formation with SV40 T‐antigen, thereby constituting a loss of wild‐type p53 function situation that allowed analysis of the postulated gain of function effects of mutant p53 R270H . We found that mutant p53 R270H in bi‐transgenic mice enhanced the transition from intraepithelial neoplasia to invasive carcinoma, resulting in a higher frequency of invasive carcinoma per gland and per mouse, a more severe tumor phenotype, and more frequent pulmonary metastasis. Surprisingly, mutant p53 R270H in this system does not increase genomic instability. Therefore, other postulated gain of function activities of mutant p53 must be responsible for the effects described here. © 2007 Wiley‐Liss, Inc.</description><issn>0020-7136</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNotkLFOwzAURS0EEqEw8AdeGVKeY2zHI6qAIhUhIZijF9spjho7ipOhG5_AN_IlpIXl3eFIV_cdQq4ZLBlAcetbsyw4Z-qEZAy0yqFg4pRkM4NcMS7PyUVKLQBjAu4y0r5MI4aR9oLTt0LBmm7RBxob2kzBjD4G2n-6EMd97-gMkHZxSm6-1u1oEwcag4lbF9zP17cPdjLO0g67Doc9NTgYH440-XRJzhrcJXf1nwvy8fjwvlrnm9en59X9JjdM6DGXQkujLUpX10aC1XXtyhKZVEpwLkvkoqm1RAQshQGpFXNWKTZ_bcGg4gty89drhpjS4JqqH_xhT8WgOkiqZknVURL_BUYHW7I</recordid><startdate>20080415</startdate><enddate>20080415</enddate><creator>Heinlein, Christina</creator><creator>Krepulat, Frauke</creator><creator>Löhler, Jürgen</creator><creator>Speidel, Daniel</creator><creator>Deppert, Wolfgang</creator><creator>Tolstonog, Genrich V.</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20080415</creationdate><title>Mutant p53 R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis</title><author>Heinlein, Christina ; Krepulat, Frauke ; Löhler, Jürgen ; Speidel, Daniel ; Deppert, Wolfgang ; Tolstonog, Genrich V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c159t-6596c9da6ebbc60d9bbe88a167753368a35fb96aa0a85c06971ed771233d0ca73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Heinlein, Christina</creatorcontrib><creatorcontrib>Krepulat, Frauke</creatorcontrib><creatorcontrib>Löhler, Jürgen</creatorcontrib><creatorcontrib>Speidel, Daniel</creatorcontrib><creatorcontrib>Deppert, Wolfgang</creatorcontrib><creatorcontrib>Tolstonog, Genrich V.</creatorcontrib><collection>CrossRef</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Heinlein, Christina</au><au>Krepulat, Frauke</au><au>Löhler, Jürgen</au><au>Speidel, Daniel</au><au>Deppert, Wolfgang</au><au>Tolstonog, Genrich V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mutant p53 R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis</atitle><jtitle>International journal of cancer</jtitle><date>2008-04-15</date><risdate>2008</risdate><volume>122</volume><issue>8</issue><spage>1701</spage><epage>1709</epage><pages>1701-1709</pages><issn>0020-7136</issn><eissn>1097-0215</eissn><abstract>In human breast cancer, mutations in the p53 gene are associated with poor prognosis. However, analysis of patient data so far did not clarify, whether missense point mutations in the p53 gene, in addition to causing loss of wild‐type p53 function, also confer a gain of function phenotype to the encoded mutant p53. As heterogeneity of patient material and data might obscure a clear answer, we studied the effects of a coexpressed mutant p53 R270H in transgenic mice in which SV40 early proteins initiate the development of mammary adenocarcinoma (WAP‐T mice). In such tumors the endogenous wild‐type p53 is functionally compromised by complex formation with SV40 T‐antigen, thereby constituting a loss of wild‐type p53 function situation that allowed analysis of the postulated gain of function effects of mutant p53 R270H . We found that mutant p53 R270H in bi‐transgenic mice enhanced the transition from intraepithelial neoplasia to invasive carcinoma, resulting in a higher frequency of invasive carcinoma per gland and per mouse, a more severe tumor phenotype, and more frequent pulmonary metastasis. Surprisingly, mutant p53 R270H in this system does not increase genomic instability. Therefore, other postulated gain of function activities of mutant p53 must be responsible for the effects described here. © 2007 Wiley‐Liss, Inc.</abstract><doi>10.1002/ijc.23317</doi><tpages>9</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0020-7136
ispartof International journal of cancer, 2008-04, Vol.122 (8), p.1701-1709
issn 0020-7136
1097-0215
language eng
recordid cdi_crossref_primary_10_1002_ijc_23317
source Wiley Journals; EZB-FREE-00999 freely available EZB journals
title Mutant p53 R270H gain of function phenotype in a mouse model for oncogene‐induced mammary carcinogenesis
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T06%3A07%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-crossref&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mutant%20p53%20R270H%20gain%20of%20function%20phenotype%20in%20a%20mouse%20model%20for%20oncogene%E2%80%90induced%20mammary%20carcinogenesis&rft.jtitle=International%20journal%20of%20cancer&rft.au=Heinlein,%20Christina&rft.date=2008-04-15&rft.volume=122&rft.issue=8&rft.spage=1701&rft.epage=1709&rft.pages=1701-1709&rft.issn=0020-7136&rft.eissn=1097-0215&rft_id=info:doi/10.1002/ijc.23317&rft_dat=%3Ccrossref%3E10_1002_ijc_23317%3C/crossref%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rfr_iscdi=true