Loading…

Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects

Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation a...

Full description

Saved in:
Bibliographic Details
Published in:Cancer cell 2004-04, Vol.5 (4), p.375-387
Main Authors: Tuveson, David A, Shaw, Alice T, Willis, Nicholas A, Silver, Daniel P, Jackson, Erica L, Chang, Sandy, Mercer, Kim L, Grochow, Rebecca, Hock, Hanno, Crowley, Denise, Hingorani, Sunil R, Zaks, Tal, King, Catrina, Jacobetz, Michael A, Wang, Lifu, Bronson, Roderick T, Orkin, Stuart H, DePinho, Ronald A, Jacks, Tyler
Format: Article
Language:English
Subjects:
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c261t-7ba64d4b9895297102e82254cab60c482a5a78e134fe8d499e3e211fbef7114d3
cites
container_end_page 387
container_issue 4
container_start_page 375
container_title Cancer cell
container_volume 5
creator Tuveson, David A
Shaw, Alice T
Willis, Nicholas A
Silver, Daniel P
Jackson, Erica L
Chang, Sandy
Mercer, Kim L
Grochow, Rebecca
Hock, Hanno
Crowley, Denise
Hingorani, Sunil R
Zaks, Tal
King, Catrina
Jacobetz, Michael A
Wang, Lifu
Bronson, Roderick T
Orkin, Stuart H
DePinho, Ronald A
Jacks, Tyler
description Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.
doi_str_mv 10.1016/S1535-6108(04)00085-6
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_71843181</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>71843181</sourcerecordid><originalsourceid>FETCH-LOGICAL-c261t-7ba64d4b9895297102e82254cab60c482a5a78e134fe8d499e3e211fbef7114d3</originalsourceid><addsrcrecordid>eNo9kEtPwzAQhH0A0VL4CaCcUHsIeG0nsY-olIKoxAE4R469QUHOg9gB8e8xz9PO7H4ajZaQE6DnQCG_eICMZ2kOVC6pWFFKZXR7ZP6_npFD719oZKFQB2QGGVU8E2JO2k1n-2fs-sknfWe-ZGOSu3TUfrkFdrVKfGjayemAPhnG3jU1jjo0fZfozibvjUU_jKht0mE_OB1p832x-IauH1rsgnbR1WiCPyL7tXYej3_ngjxdbx7XN-nufnu7vtylhuUQ0qLSubCiUlJlTBVAGUrGMmF0lVMjJNOZLiQCFzVKK5RCjgygrrAuAITlC3L2kxsbv07oQ9k23qBzOracfFmAFBwkRPD0F5yqFm05jE2rx4_y70H8E8iwZ_M</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>71843181</pqid></control><display><type>article</type><title>Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects</title><source>BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS</source><creator>Tuveson, David A ; Shaw, Alice T ; Willis, Nicholas A ; Silver, Daniel P ; Jackson, Erica L ; Chang, Sandy ; Mercer, Kim L ; Grochow, Rebecca ; Hock, Hanno ; Crowley, Denise ; Hingorani, Sunil R ; Zaks, Tal ; King, Catrina ; Jacobetz, Michael A ; Wang, Lifu ; Bronson, Roderick T ; Orkin, Stuart H ; DePinho, Ronald A ; Jacks, Tyler</creator><creatorcontrib>Tuveson, David A ; Shaw, Alice T ; Willis, Nicholas A ; Silver, Daniel P ; Jackson, Erica L ; Chang, Sandy ; Mercer, Kim L ; Grochow, Rebecca ; Hock, Hanno ; Crowley, Denise ; Hingorani, Sunil R ; Zaks, Tal ; King, Catrina ; Jacobetz, Michael A ; Wang, Lifu ; Bronson, Roderick T ; Orkin, Stuart H ; DePinho, Ronald A ; Jacks, Tyler</creatorcontrib><description>Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.</description><identifier>ISSN: 1535-6108</identifier><identifier>DOI: 10.1016/S1535-6108(04)00085-6</identifier><identifier>PMID: 15093544</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cell Cycle ; Cell Division ; Cell Transformation, Neoplastic ; Cellular Senescence ; Congenital Abnormalities - genetics ; Congenital Abnormalities - pathology ; Crosses, Genetic ; Cyclin-Dependent Kinase Inhibitor p16 ; Embryo, Mammalian - cytology ; Female ; Fibroblasts - metabolism ; Fibroblasts - pathology ; Gene Expression Regulation, Developmental - physiology ; Genes, ras - physiology ; Integrases - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Neoplasms - genetics ; Neoplasms - pathology ; Stem Cells - pathology ; Tumor Suppressor Protein p14ARF - genetics ; Tumor Suppressor Protein p14ARF - metabolism ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Viral Proteins - metabolism</subject><ispartof>Cancer cell, 2004-04, Vol.5 (4), p.375-387</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c261t-7ba64d4b9895297102e82254cab60c482a5a78e134fe8d499e3e211fbef7114d3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15093544$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tuveson, David A</creatorcontrib><creatorcontrib>Shaw, Alice T</creatorcontrib><creatorcontrib>Willis, Nicholas A</creatorcontrib><creatorcontrib>Silver, Daniel P</creatorcontrib><creatorcontrib>Jackson, Erica L</creatorcontrib><creatorcontrib>Chang, Sandy</creatorcontrib><creatorcontrib>Mercer, Kim L</creatorcontrib><creatorcontrib>Grochow, Rebecca</creatorcontrib><creatorcontrib>Hock, Hanno</creatorcontrib><creatorcontrib>Crowley, Denise</creatorcontrib><creatorcontrib>Hingorani, Sunil R</creatorcontrib><creatorcontrib>Zaks, Tal</creatorcontrib><creatorcontrib>King, Catrina</creatorcontrib><creatorcontrib>Jacobetz, Michael A</creatorcontrib><creatorcontrib>Wang, Lifu</creatorcontrib><creatorcontrib>Bronson, Roderick T</creatorcontrib><creatorcontrib>Orkin, Stuart H</creatorcontrib><creatorcontrib>DePinho, Ronald A</creatorcontrib><creatorcontrib>Jacks, Tyler</creatorcontrib><title>Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.</description><subject>Animals</subject><subject>Cell Cycle</subject><subject>Cell Division</subject><subject>Cell Transformation, Neoplastic</subject><subject>Cellular Senescence</subject><subject>Congenital Abnormalities - genetics</subject><subject>Congenital Abnormalities - pathology</subject><subject>Crosses, Genetic</subject><subject>Cyclin-Dependent Kinase Inhibitor p16</subject><subject>Embryo, Mammalian - cytology</subject><subject>Female</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - pathology</subject><subject>Gene Expression Regulation, Developmental - physiology</subject><subject>Genes, ras - physiology</subject><subject>Integrases - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Mutation</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - pathology</subject><subject>Stem Cells - pathology</subject><subject>Tumor Suppressor Protein p14ARF - genetics</subject><subject>Tumor Suppressor Protein p14ARF - metabolism</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Viral Proteins - metabolism</subject><issn>1535-6108</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><recordid>eNo9kEtPwzAQhH0A0VL4CaCcUHsIeG0nsY-olIKoxAE4R469QUHOg9gB8e8xz9PO7H4ajZaQE6DnQCG_eICMZ2kOVC6pWFFKZXR7ZP6_npFD719oZKFQB2QGGVU8E2JO2k1n-2fs-sknfWe-ZGOSu3TUfrkFdrVKfGjayemAPhnG3jU1jjo0fZfozibvjUU_jKht0mE_OB1p832x-IauH1rsgnbR1WiCPyL7tXYej3_ngjxdbx7XN-nufnu7vtylhuUQ0qLSubCiUlJlTBVAGUrGMmF0lVMjJNOZLiQCFzVKK5RCjgygrrAuAITlC3L2kxsbv07oQ9k23qBzOracfFmAFBwkRPD0F5yqFm05jE2rx4_y70H8E8iwZ_M</recordid><startdate>20040401</startdate><enddate>20040401</enddate><creator>Tuveson, David A</creator><creator>Shaw, Alice T</creator><creator>Willis, Nicholas A</creator><creator>Silver, Daniel P</creator><creator>Jackson, Erica L</creator><creator>Chang, Sandy</creator><creator>Mercer, Kim L</creator><creator>Grochow, Rebecca</creator><creator>Hock, Hanno</creator><creator>Crowley, Denise</creator><creator>Hingorani, Sunil R</creator><creator>Zaks, Tal</creator><creator>King, Catrina</creator><creator>Jacobetz, Michael A</creator><creator>Wang, Lifu</creator><creator>Bronson, Roderick T</creator><creator>Orkin, Stuart H</creator><creator>DePinho, Ronald A</creator><creator>Jacks, Tyler</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20040401</creationdate><title>Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects</title><author>Tuveson, David A ; Shaw, Alice T ; Willis, Nicholas A ; Silver, Daniel P ; Jackson, Erica L ; Chang, Sandy ; Mercer, Kim L ; Grochow, Rebecca ; Hock, Hanno ; Crowley, Denise ; Hingorani, Sunil R ; Zaks, Tal ; King, Catrina ; Jacobetz, Michael A ; Wang, Lifu ; Bronson, Roderick T ; Orkin, Stuart H ; DePinho, Ronald A ; Jacks, Tyler</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c261t-7ba64d4b9895297102e82254cab60c482a5a78e134fe8d499e3e211fbef7114d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Cell Cycle</topic><topic>Cell Division</topic><topic>Cell Transformation, Neoplastic</topic><topic>Cellular Senescence</topic><topic>Congenital Abnormalities - genetics</topic><topic>Congenital Abnormalities - pathology</topic><topic>Crosses, Genetic</topic><topic>Cyclin-Dependent Kinase Inhibitor p16</topic><topic>Embryo, Mammalian - cytology</topic><topic>Female</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - pathology</topic><topic>Gene Expression Regulation, Developmental - physiology</topic><topic>Genes, ras - physiology</topic><topic>Integrases - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Mutation</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - pathology</topic><topic>Stem Cells - pathology</topic><topic>Tumor Suppressor Protein p14ARF - genetics</topic><topic>Tumor Suppressor Protein p14ARF - metabolism</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Viral Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tuveson, David A</creatorcontrib><creatorcontrib>Shaw, Alice T</creatorcontrib><creatorcontrib>Willis, Nicholas A</creatorcontrib><creatorcontrib>Silver, Daniel P</creatorcontrib><creatorcontrib>Jackson, Erica L</creatorcontrib><creatorcontrib>Chang, Sandy</creatorcontrib><creatorcontrib>Mercer, Kim L</creatorcontrib><creatorcontrib>Grochow, Rebecca</creatorcontrib><creatorcontrib>Hock, Hanno</creatorcontrib><creatorcontrib>Crowley, Denise</creatorcontrib><creatorcontrib>Hingorani, Sunil R</creatorcontrib><creatorcontrib>Zaks, Tal</creatorcontrib><creatorcontrib>King, Catrina</creatorcontrib><creatorcontrib>Jacobetz, Michael A</creatorcontrib><creatorcontrib>Wang, Lifu</creatorcontrib><creatorcontrib>Bronson, Roderick T</creatorcontrib><creatorcontrib>Orkin, Stuart H</creatorcontrib><creatorcontrib>DePinho, Ronald A</creatorcontrib><creatorcontrib>Jacks, Tyler</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tuveson, David A</au><au>Shaw, Alice T</au><au>Willis, Nicholas A</au><au>Silver, Daniel P</au><au>Jackson, Erica L</au><au>Chang, Sandy</au><au>Mercer, Kim L</au><au>Grochow, Rebecca</au><au>Hock, Hanno</au><au>Crowley, Denise</au><au>Hingorani, Sunil R</au><au>Zaks, Tal</au><au>King, Catrina</au><au>Jacobetz, Michael A</au><au>Wang, Lifu</au><au>Bronson, Roderick T</au><au>Orkin, Stuart H</au><au>DePinho, Ronald A</au><au>Jacks, Tyler</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2004-04-01</date><risdate>2004</risdate><volume>5</volume><issue>4</issue><spage>375</spage><epage>387</epage><pages>375-387</pages><issn>1535-6108</issn><abstract>Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.</abstract><cop>United States</cop><pmid>15093544</pmid><doi>10.1016/S1535-6108(04)00085-6</doi><tpages>13</tpages></addata></record>
fulltext fulltext
identifier ISSN: 1535-6108
ispartof Cancer cell, 2004-04, Vol.5 (4), p.375-387
issn 1535-6108
language eng
recordid cdi_proquest_miscellaneous_71843181
source BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS
subjects Animals
Cell Cycle
Cell Division
Cell Transformation, Neoplastic
Cellular Senescence
Congenital Abnormalities - genetics
Congenital Abnormalities - pathology
Crosses, Genetic
Cyclin-Dependent Kinase Inhibitor p16
Embryo, Mammalian - cytology
Female
Fibroblasts - metabolism
Fibroblasts - pathology
Gene Expression Regulation, Developmental - physiology
Genes, ras - physiology
Integrases - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Neoplasms - genetics
Neoplasms - pathology
Stem Cells - pathology
Tumor Suppressor Protein p14ARF - genetics
Tumor Suppressor Protein p14ARF - metabolism
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Viral Proteins - metabolism
title Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T11%3A01%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Endogenous%20oncogenic%20K-ras(G12D)%20stimulates%20proliferation%20and%20widespread%20neoplastic%20and%20developmental%20defects&rft.jtitle=Cancer%20cell&rft.au=Tuveson,%20David%20A&rft.date=2004-04-01&rft.volume=5&rft.issue=4&rft.spage=375&rft.epage=387&rft.pages=375-387&rft.issn=1535-6108&rft_id=info:doi/10.1016/S1535-6108(04)00085-6&rft_dat=%3Cproquest_pubme%3E71843181%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c261t-7ba64d4b9895297102e82254cab60c482a5a78e134fe8d499e3e211fbef7114d3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=71843181&rft_id=info:pmid/15093544&rfr_iscdi=true