Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA
RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of...
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description | RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here, we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3-binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4E-BP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4E-BP2, which negatively regulates eukaryotic translation initiation factor 4E (eIF4E), an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP3 depletion reduced phosphorylated eIF4E, the active form, and translational efficiency of eIF4E target transcripts. Reduction of phosphorylated eIF4E by IGF2BP3 depletion was rescued by EIF4E-BP2 depletion. At last, we found an inverse correlation between the expression level of
IGF2BP3
and
EIF4E-BP2
in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA-destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E. |
doi_str_mv | 10.1038/onc.2015.410 |
format | Article |
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IGF2BP3
and
EIF4E-BP2
in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA-destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2015.410</identifier><identifier>PMID: 26522719</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/109 ; 13/89 ; 38/1 ; 45/91 ; 631/337/1645 ; 631/337/2019 ; A549 Cells ; Adenocarcinoma ; Adenocarcinoma - genetics ; Adenocarcinoma - metabolism ; Apoptosis ; Binding proteins ; Biomarkers ; Blotting, Western ; Carcinogenesis ; Cell Biology ; Cell growth ; Cell proliferation ; Cell Proliferation - genetics ; Eukaryotic Initiation Factor-4E - genetics ; Eukaryotic Initiation Factor-4E - metabolism ; Eukaryotic Initiation Factors - genetics ; Eukaryotic Initiation Factors - metabolism ; Exoribonucleases - metabolism ; Gene Expression ; Genetic aspects ; Health aspects ; HeLa Cells ; Human Genetics ; Humans ; Identification and classification ; Immunoprecipitation ; Initiation factor eIF-4E ; Internal Medicine ; Lung cancer ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Medicine ; Medicine & Public Health ; Messenger RNA ; Oncogenes ; Oncology ; original-article ; Properties ; Protein Binding ; Protein expression ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; RNA Stability - genetics ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA-binding protein ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Sequence analysis ; Tumorigenesis</subject><ispartof>Oncogene, 2016-07, Vol.35 (27), p.3495-3502</ispartof><rights>Macmillan Publishers Limited 2016</rights><rights>COPYRIGHT 2016 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 7, 2016</rights><rights>Macmillan Publishers Limited 2016.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c589t-6aafbc139905322ae4ca63c34f0c381b96255c4a65549d8534d82ae04b256d733</citedby><cites>FETCH-LOGICAL-c589t-6aafbc139905322ae4ca63c34f0c381b96255c4a65549d8534d82ae04b256d733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26522719$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mizutani, R</creatorcontrib><creatorcontrib>Imamachi, N</creatorcontrib><creatorcontrib>Suzuki, Y</creatorcontrib><creatorcontrib>Yoshida, H</creatorcontrib><creatorcontrib>Tochigi, N</creatorcontrib><creatorcontrib>Oonishi, T</creatorcontrib><creatorcontrib>Suzuki, Y</creatorcontrib><creatorcontrib>Akimitsu, N</creatorcontrib><title>Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here, we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3-binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4E-BP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4E-BP2, which negatively regulates eukaryotic translation initiation factor 4E (eIF4E), an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP3 depletion reduced phosphorylated eIF4E, the active form, and translational efficiency of eIF4E target transcripts. Reduction of phosphorylated eIF4E by IGF2BP3 depletion was rescued by EIF4E-BP2 depletion. At last, we found an inverse correlation between the expression level of
IGF2BP3
and
EIF4E-BP2
in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA-destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E.</description><subject>13/109</subject><subject>13/89</subject><subject>38/1</subject><subject>45/91</subject><subject>631/337/1645</subject><subject>631/337/2019</subject><subject>A549 Cells</subject><subject>Adenocarcinoma</subject><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - metabolism</subject><subject>Apoptosis</subject><subject>Binding proteins</subject><subject>Biomarkers</subject><subject>Blotting, Western</subject><subject>Carcinogenesis</subject><subject>Cell Biology</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - genetics</subject><subject>Eukaryotic Initiation Factor-4E - genetics</subject><subject>Eukaryotic Initiation Factor-4E - metabolism</subject><subject>Eukaryotic Initiation Factors - genetics</subject><subject>Eukaryotic Initiation Factors - metabolism</subject><subject>Exoribonucleases - metabolism</subject><subject>Gene Expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>HeLa Cells</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Identification and classification</subject><subject>Immunoprecipitation</subject><subject>Initiation factor eIF-4E</subject><subject>Internal Medicine</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Messenger RNA</subject><subject>Oncogenes</subject><subject>Oncology</subject><subject>original-article</subject><subject>Properties</subject><subject>Protein Binding</subject><subject>Protein expression</subject><subject>Proteins</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>RNA Stability - genetics</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - 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genetics</topic><topic>Adenocarcinoma - metabolism</topic><topic>Apoptosis</topic><topic>Binding proteins</topic><topic>Biomarkers</topic><topic>Blotting, Western</topic><topic>Carcinogenesis</topic><topic>Cell Biology</topic><topic>Cell growth</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - genetics</topic><topic>Eukaryotic Initiation Factor-4E - genetics</topic><topic>Eukaryotic Initiation Factor-4E - metabolism</topic><topic>Eukaryotic Initiation Factors - genetics</topic><topic>Eukaryotic Initiation Factors - metabolism</topic><topic>Exoribonucleases - metabolism</topic><topic>Gene Expression</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>HeLa Cells</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Identification and classification</topic><topic>Immunoprecipitation</topic><topic>Initiation factor eIF-4E</topic><topic>Internal Medicine</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Messenger RNA</topic><topic>Oncogenes</topic><topic>Oncology</topic><topic>original-article</topic><topic>Properties</topic><topic>Protein Binding</topic><topic>Protein expression</topic><topic>Proteins</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>RNA Stability - genetics</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>RNA-binding protein</topic><topic>RNA-Binding Proteins - genetics</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Sequence analysis</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mizutani, R</creatorcontrib><creatorcontrib>Imamachi, N</creatorcontrib><creatorcontrib>Suzuki, Y</creatorcontrib><creatorcontrib>Yoshida, H</creatorcontrib><creatorcontrib>Tochigi, N</creatorcontrib><creatorcontrib>Oonishi, T</creatorcontrib><creatorcontrib>Suzuki, Y</creatorcontrib><creatorcontrib>Akimitsu, N</creatorcontrib><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>ProQuest - 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Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mizutani, R</au><au>Imamachi, N</au><au>Suzuki, Y</au><au>Yoshida, H</au><au>Tochigi, N</au><au>Oonishi, T</au><au>Suzuki, Y</au><au>Akimitsu, N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2016-07-07</date><risdate>2016</risdate><volume>35</volume><issue>27</issue><spage>3495</spage><epage>3502</epage><pages>3495-3502</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here, we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3-binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4E-BP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4E-BP2, which negatively regulates eukaryotic translation initiation factor 4E (eIF4E), an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP3 depletion reduced phosphorylated eIF4E, the active form, and translational efficiency of eIF4E target transcripts. Reduction of phosphorylated eIF4E by IGF2BP3 depletion was rescued by EIF4E-BP2 depletion. At last, we found an inverse correlation between the expression level of
IGF2BP3
and
EIF4E-BP2
in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA-destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26522719</pmid><doi>10.1038/onc.2015.410</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 13/109 13/89 38/1 45/91 631/337/1645 631/337/2019 A549 Cells Adenocarcinoma Adenocarcinoma - genetics Adenocarcinoma - metabolism Apoptosis Binding proteins Biomarkers Blotting, Western Carcinogenesis Cell Biology Cell growth Cell proliferation Cell Proliferation - genetics Eukaryotic Initiation Factor-4E - genetics Eukaryotic Initiation Factor-4E - metabolism Eukaryotic Initiation Factors - genetics Eukaryotic Initiation Factors - metabolism Exoribonucleases - metabolism Gene Expression Genetic aspects Health aspects HeLa Cells Human Genetics Humans Identification and classification Immunoprecipitation Initiation factor eIF-4E Internal Medicine Lung cancer Lung Neoplasms - genetics Lung Neoplasms - metabolism Medicine Medicine & Public Health Messenger RNA Oncogenes Oncology original-article Properties Protein Binding Protein expression Proteins Reverse Transcriptase Polymerase Chain Reaction RNA Interference RNA Stability - genetics RNA, Messenger - genetics RNA, Messenger - metabolism RNA-binding protein RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Sequence analysis Tumorigenesis |
title | Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA |
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