KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors
Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH ( e rythropoietin- p roduci...
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| Veröffentlicht in: | Molecular and cellular biology 2016-09, Vol.36 (17), p.2246-2261 |
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| creator | McCall, Jamie L. Gehring, Drew Clymer, Beth K. Fisher, Kurt W. Das, Binita Kelly, David L. Kim, Hyunseok White, Michael A. Lewis, Robert E. |
| description | Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (
e
rythropoietin-
p
roducing
h
epatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors. |
| doi_str_mv | 10.1128/MCB.00087-16 |
| format | Article |
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e
rythropoietin-
p
roducing
h
epatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.</description><identifier>ISSN: 1098-5549</identifier><identifier>ISSN: 0270-7306</identifier><identifier>EISSN: 1098-5549</identifier><identifier>DOI: 10.1128/MCB.00087-16</identifier><identifier>PMID: 27273865</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Caco-2 Cells ; Carrier Proteins - genetics ; Cell Line, Tumor ; Cell Survival ; Colonic Neoplasms - metabolism ; Gene Expression Regulation, Neoplastic ; HCT116 Cells ; Humans ; Protein Kinases - metabolism ; Proto-Oncogene Proteins c-myc - genetics ; Receptor, EphB4 - metabolism ; RNA Processing, Post-Transcriptional ; Spotlight ; Up-Regulation</subject><ispartof>Molecular and cellular biology, 2016-09, Vol.36 (17), p.2246-2261</ispartof><rights>Copyright © 2016, American Society for Microbiology 2016</rights><rights>Copyright © 2016, American Society for Microbiology. All Rights Reserved.</rights><rights>Copyright © 2016, American Society for Microbiology. All Rights Reserved. 2016 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c432t-5bf029cecf9e71b7c1edb766c269deb1a9d59ec3b9070c9af5f0c4fa23ccb3033</citedby><cites>FETCH-LOGICAL-c432t-5bf029cecf9e71b7c1edb766c269deb1a9d59ec3b9070c9af5f0c4fa23ccb3033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985931/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985931/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27273865$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McCall, Jamie L.</creatorcontrib><creatorcontrib>Gehring, Drew</creatorcontrib><creatorcontrib>Clymer, Beth K.</creatorcontrib><creatorcontrib>Fisher, Kurt W.</creatorcontrib><creatorcontrib>Das, Binita</creatorcontrib><creatorcontrib>Kelly, David L.</creatorcontrib><creatorcontrib>Kim, Hyunseok</creatorcontrib><creatorcontrib>White, Michael A.</creatorcontrib><creatorcontrib>Lewis, Robert E.</creatorcontrib><title>KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors</title><title>Molecular and cellular biology</title><addtitle>Mol Cell Biol</addtitle><description>Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (
e
rythropoietin-
p
roducing
h
epatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.</description><subject>Caco-2 Cells</subject><subject>Carrier Proteins - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>HCT116 Cells</subject><subject>Humans</subject><subject>Protein Kinases - metabolism</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Receptor, EphB4 - metabolism</subject><subject>RNA Processing, Post-Transcriptional</subject><subject>Spotlight</subject><subject>Up-Regulation</subject><issn>1098-5549</issn><issn>0270-7306</issn><issn>1098-5549</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkNFOwjAUhhujEUTvvDZ9AIftuq3rjYksCEaIC-B103Utzmwr6TYIr-WD-ExOUIKJV-fknO98J_kBuMaoj7Eb3k2jQR8hFFIHByegixELHd_32OlR3wEXVfXeUgFD5Bx0XOpSEgZ-F8TP8xmGokzhMB4PPDhTyyYXtYLTrdyN41GEPz_gwsDYmsK0m3lj19la5NBoOG4KUcLI5KaEi6YwtroEZ1rklbr6qT3w-jhcRGNn8jJ6ih4mjvSIWzt-opHLpJKaKYoTKrFKExoE0g1YqhIsWOozJUnCEEWSCe1rJD0tXCJlQhAhPXC_966apFCpVGVtRc5XNiuE3XIjMv53U2ZvfGnW3GOhzwhuBbd7gbSmqqzSh1uM-HeyvE2W75LlOGjxm-N_B_g3yhageyArtbGF2Bibp7wW29xYbUUps4qTf9VfbRWHMw</recordid><startdate>20160901</startdate><enddate>20160901</enddate><creator>McCall, Jamie L.</creator><creator>Gehring, Drew</creator><creator>Clymer, Beth K.</creator><creator>Fisher, Kurt W.</creator><creator>Das, Binita</creator><creator>Kelly, David L.</creator><creator>Kim, Hyunseok</creator><creator>White, Michael A.</creator><creator>Lewis, Robert E.</creator><general>Taylor & Francis</general><general>American Society for Microbiology</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>20160901</creationdate><title>KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors</title><author>McCall, Jamie L. ; Gehring, Drew ; Clymer, Beth K. ; Fisher, Kurt W. ; Das, Binita ; Kelly, David L. ; Kim, Hyunseok ; White, Michael A. ; Lewis, Robert E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c432t-5bf029cecf9e71b7c1edb766c269deb1a9d59ec3b9070c9af5f0c4fa23ccb3033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Caco-2 Cells</topic><topic>Carrier Proteins - genetics</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>HCT116 Cells</topic><topic>Humans</topic><topic>Protein Kinases - metabolism</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Receptor, EphB4 - metabolism</topic><topic>RNA Processing, Post-Transcriptional</topic><topic>Spotlight</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McCall, Jamie L.</creatorcontrib><creatorcontrib>Gehring, Drew</creatorcontrib><creatorcontrib>Clymer, Beth K.</creatorcontrib><creatorcontrib>Fisher, Kurt W.</creatorcontrib><creatorcontrib>Das, Binita</creatorcontrib><creatorcontrib>Kelly, David L.</creatorcontrib><creatorcontrib>Kim, Hyunseok</creatorcontrib><creatorcontrib>White, Michael A.</creatorcontrib><creatorcontrib>Lewis, Robert E.</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>Molecular and cellular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McCall, Jamie L.</au><au>Gehring, Drew</au><au>Clymer, Beth K.</au><au>Fisher, Kurt W.</au><au>Das, Binita</au><au>Kelly, David L.</au><au>Kim, Hyunseok</au><au>White, Michael A.</au><au>Lewis, Robert E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors</atitle><jtitle>Molecular and cellular biology</jtitle><addtitle>Mol Cell Biol</addtitle><date>2016-09-01</date><risdate>2016</risdate><volume>36</volume><issue>17</issue><spage>2246</spage><epage>2261</epage><pages>2246-2261</pages><issn>1098-5549</issn><issn>0270-7306</issn><eissn>1098-5549</eissn><abstract>Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (
e
rythropoietin-
p
roducing
h
epatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>27273865</pmid><doi>10.1128/MCB.00087-16</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Caco-2 Cells Carrier Proteins - genetics Cell Line, Tumor Cell Survival Colonic Neoplasms - metabolism Gene Expression Regulation, Neoplastic HCT116 Cells Humans Protein Kinases - metabolism Proto-Oncogene Proteins c-myc - genetics Receptor, EphB4 - metabolism RNA Processing, Post-Transcriptional Spotlight Up-Regulation |
| title | KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors |
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