Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation
Backgrounds/Aims Insulin receptor substrate-4 (IRS-4) is a scaffold protein that mediates the actions of insulin-like growth factor-I (IGF-I). Its expression increases dramatically after partial hepatectomy (a liver regeneration model). Herein, we report IRS-4 expression in a human hepatoblastoma ce...
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| Veröffentlicht in: | Journal of hepatology 2007-06, Vol.46 (6), p.1089-1098 |
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| creator | Cuevas, Eva P Escribano, Oscar Chiloeches, Antonio Ramirez Rubio, Sara Román, Irene Dolores Fernández-Moreno, María Dolores Guijarro, Luis G |
| description | Backgrounds/Aims Insulin receptor substrate-4 (IRS-4) is a scaffold protein that mediates the actions of insulin-like growth factor-I (IGF-I). Its expression increases dramatically after partial hepatectomy (a liver regeneration model). Herein, we report IRS-4 expression in a human hepatoblastoma cell line (HepG2) and IGF-I-dependent IRS-4 tyrosine phosphorylation. Methods The role of IRS-4 in HepG2 proliferation was established by RNA interference (siRNA). After 72 h of transfection with IRS-4 siRNA, we observed a specific reduction in IRS-4 expression. Results Depletion of IRS-4 levels decreased ERK phosphorylation, p70S6K phosphorylation and IGF-I-stimulated cell proliferation. Changes in ERK phosphorylation in IRS-4-depleted cells were independent of ras/raf/MEK1/2- and PI3K/Akt-cascades. IRS-4 down-regulation abolished IGF-I-, TPA- and IGF-I plus TPA-stimulated ERK and p70S6K activities. Our results suggest that PKC- ε mediates the effect of IRS-4 on ERK activity. Moreover, decreased IRS-4 levels diminished FBS- and IGF-I-stimulated HepG2 growth and cause stress fiber disruption in HepG2 cell line. Conclusions Collectively, our data suggest that IRS-4 plays an important role in HepG2 proliferation/differentiation and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2- and PI3Kinase/Akt-independent manner and in a PKC-dependent way. |
| doi_str_mv | 10.1016/j.jhep.2007.01.031 |
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Its expression increases dramatically after partial hepatectomy (a liver regeneration model). Herein, we report IRS-4 expression in a human hepatoblastoma cell line (HepG2) and IGF-I-dependent IRS-4 tyrosine phosphorylation. Methods The role of IRS-4 in HepG2 proliferation was established by RNA interference (siRNA). After 72 h of transfection with IRS-4 siRNA, we observed a specific reduction in IRS-4 expression. Results Depletion of IRS-4 levels decreased ERK phosphorylation, p70S6K phosphorylation and IGF-I-stimulated cell proliferation. Changes in ERK phosphorylation in IRS-4-depleted cells were independent of ras/raf/MEK1/2- and PI3K/Akt-cascades. IRS-4 down-regulation abolished IGF-I-, TPA- and IGF-I plus TPA-stimulated ERK and p70S6K activities. Our results suggest that PKC- ε mediates the effect of IRS-4 on ERK activity. Moreover, decreased IRS-4 levels diminished FBS- and IGF-I-stimulated HepG2 growth and cause stress fiber disruption in HepG2 cell line. Conclusions Collectively, our data suggest that IRS-4 plays an important role in HepG2 proliferation/differentiation and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2- and PI3Kinase/Akt-independent manner and in a PKC-dependent way.</description><identifier>ISSN: 0168-8278</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2007.01.031</identifier><identifier>PMID: 17408801</identifier><identifier>CODEN: JOHEEC</identifier><language>eng</language><publisher>Oxford: Elsevier B.V</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Biological and medical sciences ; Cell Line, Tumor ; Cell Proliferation ; Gastroenterology and Hepatology ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression Regulation ; Hepatectomy ; Hepatocytes - cytology ; HepG2 ; Humans ; IGF-I ; Insulin Receptor Substrate Proteins ; Insulin-Like Growth Factor I - metabolism ; IRS-4 ; Liver - pathology ; Liver, biliary tract, pancreas, portal circulation, spleen ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; MAPK ; Medical sciences ; Microscopy, Phase-Contrast ; Models, Biological ; Other diseases. Semiology ; Phosphorylation ; Protein Kinase C - metabolism ; siRNA ; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases ; Surgery of the digestive system ; Time Factors ; Transfection</subject><ispartof>Journal of hepatology, 2007-06, Vol.46 (6), p.1089-1098</ispartof><rights>European Association for the Study of the Liver</rights><rights>2007 European Association for the Study of the Liver</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c505t-376ab213672197b77a0ea283d84f2860e8781eac150219d99daf4cc2f32be7f43</citedby><cites>FETCH-LOGICAL-c505t-376ab213672197b77a0ea283d84f2860e8781eac150219d99daf4cc2f32be7f43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jhep.2007.01.031$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18768334$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17408801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cuevas, Eva P</creatorcontrib><creatorcontrib>Escribano, Oscar</creatorcontrib><creatorcontrib>Chiloeches, Antonio</creatorcontrib><creatorcontrib>Ramirez Rubio, Sara</creatorcontrib><creatorcontrib>Román, Irene Dolores</creatorcontrib><creatorcontrib>Fernández-Moreno, María Dolores</creatorcontrib><creatorcontrib>Guijarro, Luis G</creatorcontrib><title>Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>Backgrounds/Aims Insulin receptor substrate-4 (IRS-4) is a scaffold protein that mediates the actions of insulin-like growth factor-I (IGF-I). Its expression increases dramatically after partial hepatectomy (a liver regeneration model). Herein, we report IRS-4 expression in a human hepatoblastoma cell line (HepG2) and IGF-I-dependent IRS-4 tyrosine phosphorylation. Methods The role of IRS-4 in HepG2 proliferation was established by RNA interference (siRNA). After 72 h of transfection with IRS-4 siRNA, we observed a specific reduction in IRS-4 expression. Results Depletion of IRS-4 levels decreased ERK phosphorylation, p70S6K phosphorylation and IGF-I-stimulated cell proliferation. Changes in ERK phosphorylation in IRS-4-depleted cells were independent of ras/raf/MEK1/2- and PI3K/Akt-cascades. IRS-4 down-regulation abolished IGF-I-, TPA- and IGF-I plus TPA-stimulated ERK and p70S6K activities. Our results suggest that PKC- ε mediates the effect of IRS-4 on ERK activity. Moreover, decreased IRS-4 levels diminished FBS- and IGF-I-stimulated HepG2 growth and cause stress fiber disruption in HepG2 cell line. Conclusions Collectively, our data suggest that IRS-4 plays an important role in HepG2 proliferation/differentiation and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2- and PI3Kinase/Akt-independent manner and in a PKC-dependent way.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Gastroenterology and Hepatology</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression Regulation</subject><subject>Hepatectomy</subject><subject>Hepatocytes - cytology</subject><subject>HepG2</subject><subject>Humans</subject><subject>IGF-I</subject><subject>Insulin Receptor Substrate Proteins</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>IRS-4</subject><subject>Liver - pathology</subject><subject>Liver, biliary tract, pancreas, portal circulation, spleen</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>MAPK</subject><subject>Medical sciences</subject><subject>Microscopy, Phase-Contrast</subject><subject>Models, Biological</subject><subject>Other diseases. Semiology</subject><subject>Phosphorylation</subject><subject>Protein Kinase C - metabolism</subject><subject>siRNA</subject><subject>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</subject><subject>Surgery of the digestive system</subject><subject>Time Factors</subject><subject>Transfection</subject><issn>0168-8278</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFq3DAQhkVIaLZpXyCH4kt6szuSbEuGECgh2SwspLTJWcjyiMrxWhvJLuTtK7MLgR56Eoy-f2b4hpBLCgUFWn_ri_437gsGIAqgBXB6Qla0BsihLukpWSVI5pIJeU4-xtgDAIem_EDOqShBSqArsv3pB8y8zdwY58GNWUCD-8mHLM5tnIKeMC_TZ7ZZ3-ebPE5uNw-p2GUPdz_WLNsHPziLiXN-_ETOrB4ifj6-F-T5_u7p9iHfPq43t9-3uamgmnIuat0yymvBaCNaITSgZpJ3srRM1oBSSIra0AoS0DVNp21pDLOctShsyS_I10PfNP11xjipnYsGh0GP6OeoBJR1VTVNAtkBNMHHGNCqfXA7Hd4UBbU4VL1aHKrFoQKqksMU-nLsPrc77N4jR2kJuDoCOho92KBH4-I7J0UtOV_WvD5wmFz8cRhUNA5Hg51LlifVeff_PW7-iZt0IJcmvuAbxt7PYUyWFVWRKVC_lmsvxwYBQEEC_wtTfqKe</recordid><startdate>20070601</startdate><enddate>20070601</enddate><creator>Cuevas, Eva P</creator><creator>Escribano, Oscar</creator><creator>Chiloeches, Antonio</creator><creator>Ramirez Rubio, Sara</creator><creator>Román, Irene Dolores</creator><creator>Fernández-Moreno, María Dolores</creator><creator>Guijarro, Luis G</creator><general>Elsevier B.V</general><general>Elsevier</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>7X8</scope></search><sort><creationdate>20070601</creationdate><title>Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation</title><author>Cuevas, Eva P ; Escribano, Oscar ; Chiloeches, Antonio ; Ramirez Rubio, Sara ; Román, Irene Dolores ; Fernández-Moreno, María Dolores ; Guijarro, Luis G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c505t-376ab213672197b77a0ea283d84f2860e8781eac150219d99daf4cc2f32be7f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Gastroenterology and Hepatology</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression Regulation</topic><topic>Hepatectomy</topic><topic>Hepatocytes - cytology</topic><topic>HepG2</topic><topic>Humans</topic><topic>IGF-I</topic><topic>Insulin Receptor Substrate Proteins</topic><topic>Insulin-Like Growth Factor I - metabolism</topic><topic>IRS-4</topic><topic>Liver - pathology</topic><topic>Liver, biliary tract, pancreas, portal circulation, spleen</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>MAPK</topic><topic>Medical sciences</topic><topic>Microscopy, Phase-Contrast</topic><topic>Models, Biological</topic><topic>Other diseases. Semiology</topic><topic>Phosphorylation</topic><topic>Protein Kinase C - metabolism</topic><topic>siRNA</topic><topic>Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases</topic><topic>Surgery of the digestive system</topic><topic>Time Factors</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cuevas, Eva P</creatorcontrib><creatorcontrib>Escribano, Oscar</creatorcontrib><creatorcontrib>Chiloeches, Antonio</creatorcontrib><creatorcontrib>Ramirez Rubio, Sara</creatorcontrib><creatorcontrib>Román, Irene Dolores</creatorcontrib><creatorcontrib>Fernández-Moreno, María Dolores</creatorcontrib><creatorcontrib>Guijarro, Luis G</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>MEDLINE - Academic</collection><jtitle>Journal of hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cuevas, Eva P</au><au>Escribano, Oscar</au><au>Chiloeches, Antonio</au><au>Ramirez Rubio, Sara</au><au>Román, Irene Dolores</au><au>Fernández-Moreno, María Dolores</au><au>Guijarro, Luis G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2007-06-01</date><risdate>2007</risdate><volume>46</volume><issue>6</issue><spage>1089</spage><epage>1098</epage><pages>1089-1098</pages><issn>0168-8278</issn><eissn>1600-0641</eissn><coden>JOHEEC</coden><abstract>Backgrounds/Aims Insulin receptor substrate-4 (IRS-4) is a scaffold protein that mediates the actions of insulin-like growth factor-I (IGF-I). Its expression increases dramatically after partial hepatectomy (a liver regeneration model). Herein, we report IRS-4 expression in a human hepatoblastoma cell line (HepG2) and IGF-I-dependent IRS-4 tyrosine phosphorylation. Methods The role of IRS-4 in HepG2 proliferation was established by RNA interference (siRNA). After 72 h of transfection with IRS-4 siRNA, we observed a specific reduction in IRS-4 expression. Results Depletion of IRS-4 levels decreased ERK phosphorylation, p70S6K phosphorylation and IGF-I-stimulated cell proliferation. Changes in ERK phosphorylation in IRS-4-depleted cells were independent of ras/raf/MEK1/2- and PI3K/Akt-cascades. IRS-4 down-regulation abolished IGF-I-, TPA- and IGF-I plus TPA-stimulated ERK and p70S6K activities. Our results suggest that PKC- ε mediates the effect of IRS-4 on ERK activity. Moreover, decreased IRS-4 levels diminished FBS- and IGF-I-stimulated HepG2 growth and cause stress fiber disruption in HepG2 cell line. Conclusions Collectively, our data suggest that IRS-4 plays an important role in HepG2 proliferation/differentiation and exerts its actions through ERK and p70S6K activation in a ras/raf/MEK1/2- and PI3Kinase/Akt-independent manner and in a PKC-dependent way.</abstract><cop>Oxford</cop><pub>Elsevier B.V</pub><pmid>17408801</pmid><doi>10.1016/j.jhep.2007.01.031</doi><tpages>10</tpages></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - metabolism Biological and medical sciences Cell Line, Tumor Cell Proliferation Gastroenterology and Hepatology Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Regulation Hepatectomy Hepatocytes - cytology HepG2 Humans IGF-I Insulin Receptor Substrate Proteins Insulin-Like Growth Factor I - metabolism IRS-4 Liver - pathology Liver, biliary tract, pancreas, portal circulation, spleen Liver. Biliary tract. Portal circulation. Exocrine pancreas MAPK Medical sciences Microscopy, Phase-Contrast Models, Biological Other diseases. Semiology Phosphorylation Protein Kinase C - metabolism siRNA Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases Surgery of the digestive system Time Factors Transfection |
| title | Role of insulin receptor substrate-4 in IGF-I-stimulated HEPG2 proliferation |
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