Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation
Mutations in receptor tyrosine kinase (RTK) growth factor receptors ( epidermal growth factor receptor , platelet-derived growth factor receptor , MET and ERBB2) , which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are...
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| Veröffentlicht in: | Oncogene 2010-01, Vol.29 (3), p.335-344 |
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| creator | Robinson, J P VanBrocklin, M W Guilbeault, A R Signorelli, D L Brandner, S Holmen, S L |
| description | Mutations in receptor tyrosine kinase (RTK) growth factor receptors (
epidermal growth factor receptor
,
platelet-derived growth factor receptor
,
MET
and
ERBB2)
, which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral
r
eplication-
c
ompetent
a
vian leukosis virus long terminal repeat,
s
plice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in
Ink4a/Arf
lox/lox
mice
in vivo
. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with
Ink4a/Arf
loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not
Ink4a/Arf
loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy. |
| doi_str_mv | 10.1038/onc.2009.333 |
| format | Article |
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epidermal growth factor receptor
,
platelet-derived growth factor receptor
,
MET
and
ERBB2)
, which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral
r
eplication-
c
ompetent
a
vian leukosis virus long terminal repeat,
s
plice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in
Ink4a/Arf
lox/lox
mice
in vivo
. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with
Ink4a/Arf
loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not
Ink4a/Arf
loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2009.333</identifier><identifier>PMID: 19855433</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Apoptosis ; Astrocytes - cytology ; Astrocytes - metabolism ; Avian leukosis virus ; Biological and medical sciences ; Blotting, Western ; Brain cancer ; Cell Biology ; Cell Line ; Cell physiology ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Cyclin-Dependent Kinase Inhibitor p16 - metabolism ; Enzyme Activation ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; Genetic aspects ; Genetics ; Glioma - genetics ; Glioma - metabolism ; Glioma - pathology ; Gliomas ; Growth factor receptors ; Human Genetics ; Immunohistochemistry ; Internal Medicine ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinases - metabolism ; Molecular and cellular biology ; Mutation ; Neurology ; Oncology ; original-article ; Physiological aspects ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins B-raf - metabolism ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins p21(ras) - genetics ; Proto-Oncogene Proteins p21(ras) - metabolism ; Risk factors ; Rodents ; Signal transduction ; Transfection ; Tumors of the nervous system. Phacomatoses</subject><ispartof>Oncogene, 2010-01, Vol.29 (3), p.335-344</ispartof><rights>Macmillan Publishers Limited 2010</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2010 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 21, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c576t-13a1a2124ebd0e55a4592967f54110e72f24f8eeea94fb4a59e8421d87ff48033</citedby><cites>FETCH-LOGICAL-c576t-13a1a2124ebd0e55a4592967f54110e72f24f8eeea94fb4a59e8421d87ff48033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2009.333$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2009.333$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22398160$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19855433$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Robinson, J P</creatorcontrib><creatorcontrib>VanBrocklin, M W</creatorcontrib><creatorcontrib>Guilbeault, A R</creatorcontrib><creatorcontrib>Signorelli, D L</creatorcontrib><creatorcontrib>Brandner, S</creatorcontrib><creatorcontrib>Holmen, S L</creatorcontrib><title>Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Mutations in receptor tyrosine kinase (RTK) growth factor receptors (
epidermal growth factor receptor
,
platelet-derived growth factor receptor
,
MET
and
ERBB2)
, which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral
r
eplication-
c
ompetent
a
vian leukosis virus long terminal repeat,
s
plice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in
Ink4a/Arf
lox/lox
mice
in vivo
. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with
Ink4a/Arf
loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not
Ink4a/Arf
loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Astrocytes - cytology</subject><subject>Astrocytes - metabolism</subject><subject>Avian leukosis virus</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Brain cancer</subject><subject>Cell Biology</subject><subject>Cell Line</subject><subject>Cell physiology</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cells, Cultured</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</subject><subject>Enzyme Activation</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene mutations</subject><subject>Genetic aspects</subject><subject>Genetics</subject><subject>Glioma - genetics</subject><subject>Glioma - metabolism</subject><subject>Glioma - pathology</subject><subject>Gliomas</subject><subject>Growth factor receptors</subject><subject>Human Genetics</subject><subject>Immunohistochemistry</subject><subject>Internal Medicine</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Molecular and cellular biology</subject><subject>Mutation</subject><subject>Neurology</subject><subject>Oncology</subject><subject>original-article</subject><subject>Physiological aspects</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Proto-Oncogene Proteins B-raf - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Transfection</subject><subject>Tumors of the nervous system. Phacomatoses</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9ks9rFDEUx4Modl29eZagqBdnm58zk4swLVYLBUH04iVkMy-7aWeSNplt6X9vll1aK0UCCcn7vO9LXr4IvaZkQQlvD2OwC0aIWnDOn6AZFU1dSanEUzQjSpJKMc4O0IuczwkhjSLsOTqgqpVScD5Dvzs7-WszQY-PfnQn2Id-YyHj1eDjaHLZ49FbwDdrCNjGcelDQW_8tMan4UKYwy45PMSccUy4u5iw2en5GF6iZ84MGV7t1zn6dfLl5_G36uz719Pj7qyysqmninJDDaNMwLInIKURUjFVN04KSgk0zDHhWgAwSrilMFJBKxjt28Y50RLO5-jzTvdysxyhtxCmZAZ9mfxo0q2OxuuHkeDXehWvtaBEKUWLwMe9QIpXG8iTHn22MAwmQNxk3XDBBG_FttSH_5KMciKZlAV8-w94HjcplDZoxopeq8o8R-920MoMoH1wsVzPbhV1x2jTirqm25qLR6gyeig_EwM4X84fJHzaJdhU_iWBu2sFJXprGV0so7eW0cUyBX_zd_vu4b1HCvB-D5hszeCSCdbnO44xrlpak8JVOy6XUFhBun_zo4X_AGtS1Y4</recordid><startdate>20100121</startdate><enddate>20100121</enddate><creator>Robinson, J P</creator><creator>VanBrocklin, M W</creator><creator>Guilbeault, A R</creator><creator>Signorelli, D L</creator><creator>Brandner, S</creator><creator>Holmen, S L</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</scope><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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7TK</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100121</creationdate><title>Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation</title><author>Robinson, J P ; VanBrocklin, M W ; Guilbeault, A R ; Signorelli, D L ; Brandner, S ; Holmen, S L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c576t-13a1a2124ebd0e55a4592967f54110e72f24f8eeea94fb4a59e8421d87ff48033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Astrocytes - cytology</topic><topic>Astrocytes - metabolism</topic><topic>Avian leukosis virus</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Brain cancer</topic><topic>Cell Biology</topic><topic>Cell Line</topic><topic>Cell physiology</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cells, Cultured</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</topic><topic>Enzyme Activation</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene mutations</topic><topic>Genetic aspects</topic><topic>Genetics</topic><topic>Glioma - genetics</topic><topic>Glioma - metabolism</topic><topic>Glioma - pathology</topic><topic>Gliomas</topic><topic>Growth factor receptors</topic><topic>Human Genetics</topic><topic>Immunohistochemistry</topic><topic>Internal Medicine</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Molecular and cellular biology</topic><topic>Mutation</topic><topic>Neurology</topic><topic>Oncology</topic><topic>original-article</topic><topic>Physiological aspects</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>Proto-Oncogene Proteins B-raf - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>Risk factors</topic><topic>Rodents</topic><topic>Signal transduction</topic><topic>Transfection</topic><topic>Tumors of the nervous system. Phacomatoses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Robinson, J P</creatorcontrib><creatorcontrib>VanBrocklin, M W</creatorcontrib><creatorcontrib>Guilbeault, A R</creatorcontrib><creatorcontrib>Signorelli, D L</creatorcontrib><creatorcontrib>Brandner, S</creatorcontrib><creatorcontrib>Holmen, S L</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Robinson, J P</au><au>VanBrocklin, M W</au><au>Guilbeault, A R</au><au>Signorelli, D L</au><au>Brandner, S</au><au>Holmen, S L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2010-01-21</date><risdate>2010</risdate><volume>29</volume><issue>3</issue><spage>335</spage><epage>344</epage><pages>335-344</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Mutations in receptor tyrosine kinase (RTK) growth factor receptors (
epidermal growth factor receptor
,
platelet-derived growth factor receptor
,
MET
and
ERBB2)
, which result in downstream activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral
r
eplication-
c
ompetent
a
vian leukosis virus long terminal repeat,
s
plice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in
Ink4a/Arf
lox/lox
mice
in vivo
. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with
Ink4a/Arf
loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not
Ink4a/Arf
loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>19855433</pmid><doi>10.1038/onc.2009.333</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2010-01, Vol.29 (3), p.335-344 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4109991 |
| source | MEDLINE; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SpringerLink Journals - AutoHoldings |
| subjects | Animals Apoptosis Astrocytes - cytology Astrocytes - metabolism Avian leukosis virus Biological and medical sciences Blotting, Western Brain cancer Cell Biology Cell Line Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16 - genetics Cyclin-Dependent Kinase Inhibitor p16 - metabolism Enzyme Activation Fundamental and applied biological sciences. Psychology Gene mutations Genetic aspects Genetics Glioma - genetics Glioma - metabolism Glioma - pathology Gliomas Growth factor receptors Human Genetics Immunohistochemistry Internal Medicine Medical sciences Medicine Medicine & Public Health Mice Mice, Transgenic Mitogen-Activated Protein Kinases - metabolism Molecular and cellular biology Mutation Neurology Oncology original-article Physiological aspects Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism Risk factors Rodents Signal transduction Transfection Tumors of the nervous system. Phacomatoses |
| title | Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation |
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