GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation
Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We invest...
Gespeichert in:
| Veröffentlicht in: | Genes & development 2009-01, Vol.23 (1), p.24-36 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 36 |
|---|---|
| container_issue | 1 |
| container_start_page | 24 |
| container_title | Genes & development |
| container_volume | 23 |
| creator | Nolan-Stevaux, Olivier Lau, Janet Truitt, Morgan L Chu, Gerald C Hebrok, Matthias Fernández-Zapico, Martin E Hanahan, Douglas |
| description | Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh-Ptch-Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh-Ptch-Smo signaling and is regulated by TGF-beta and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells. |
| doi_str_mv | 10.1101/gad.1753809 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2632164</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>20390570</sourcerecordid><originalsourceid>FETCH-LOGICAL-c476t-54e4b8428362a1c9428575bee12c0cff99ec78924bb936bae80da6c7a69c1a0c3</originalsourceid><addsrcrecordid>eNpVkU9P3DAQxS3UChboqffKp16qgJ0_TnyphLYtIK1UJOjZmjiTjavETm1nJT5EvzNeWFF6sUean9_M8yPkI2cXnDN-uYXugtdV0TB5RFa8KmVWlXX9jqxYI1kmCyFPyGkIvxljgglxTE645IUQebkif683t5yaQD1ulxEidjQO3i3bgd5PzsUBLXaZsR3OmA4b6YR6AGvCFKix1KKbRwjRaDqD1R5hX3aLjoGC7RLdmaQa6N23qzXVOI40LH5ndjA-96MHG3rnp_TO2XPyvocx4IfDfUZ-_fj-sL7JNj-vb9dXm0yXtYjJHpZtU-ZNIXLgWqaqqqsWkeea6b6XEnXdyLxs2-S-BWxYB0LXIKTmwHRxRr6-6M5LmzbUyZeHUc3eTOAflQOj_u9YM6it26lcFDkXZRL4fBDw7s-CIarJhL07SB-yBJWzQrKqZgn88gJq70Lw2L8O4Uzt41MpPnWIL9Gf3u71jz3kVTwBs8aaTg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20390570</pqid></control><display><type>article</type><title>GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation</title><source>PubMed Central Free</source><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Nolan-Stevaux, Olivier ; Lau, Janet ; Truitt, Morgan L ; Chu, Gerald C ; Hebrok, Matthias ; Fernández-Zapico, Martin E ; Hanahan, Douglas</creator><creatorcontrib>Nolan-Stevaux, Olivier ; Lau, Janet ; Truitt, Morgan L ; Chu, Gerald C ; Hebrok, Matthias ; Fernández-Zapico, Martin E ; Hanahan, Douglas</creatorcontrib><description>Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh-Ptch-Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh-Ptch-Smo signaling and is regulated by TGF-beta and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.1753809</identifier><identifier>PMID: 19136624</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Animals ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - metabolism ; Carcinoma, Pancreatic Ductal - pathology ; Cell Line ; Cell Survival ; Cell Transformation, Neoplastic - metabolism ; Cells, Cultured ; Gene Expression Regulation, Neoplastic ; Hedgehog Proteins - genetics ; Hedgehog Proteins - metabolism ; Humans ; Kruppel-Like Transcription Factors - genetics ; Kruppel-Like Transcription Factors - metabolism ; Mice ; Pancreatic Ducts - metabolism ; Pancreatic Ducts - pathology ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Proto-Oncogene Proteins p21(ras) - metabolism ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Research Paper ; Signal Transduction ; Smoothened Receptor ; Transforming Growth Factor beta - metabolism ; Zinc Finger Protein GLI1</subject><ispartof>Genes & development, 2009-01, Vol.23 (1), p.24-36</ispartof><rights>Copyright © 2009 by Cold Spring Harbor Laboratory Press 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c476t-54e4b8428362a1c9428575bee12c0cff99ec78924bb936bae80da6c7a69c1a0c3</citedby><cites>FETCH-LOGICAL-c476t-54e4b8428362a1c9428575bee12c0cff99ec78924bb936bae80da6c7a69c1a0c3</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/PMC2632164/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632164/$$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/19136624$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nolan-Stevaux, Olivier</creatorcontrib><creatorcontrib>Lau, Janet</creatorcontrib><creatorcontrib>Truitt, Morgan L</creatorcontrib><creatorcontrib>Chu, Gerald C</creatorcontrib><creatorcontrib>Hebrok, Matthias</creatorcontrib><creatorcontrib>Fernández-Zapico, Martin E</creatorcontrib><creatorcontrib>Hanahan, Douglas</creatorcontrib><title>GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh-Ptch-Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh-Ptch-Smo signaling and is regulated by TGF-beta and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells.</description><subject>Animals</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - metabolism</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Line</subject><subject>Cell Survival</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cells, Cultured</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Hedgehog Proteins - genetics</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Humans</subject><subject>Kruppel-Like Transcription Factors - genetics</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Mice</subject><subject>Pancreatic Ducts - metabolism</subject><subject>Pancreatic Ducts - pathology</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Research Paper</subject><subject>Signal Transduction</subject><subject>Smoothened Receptor</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Zinc Finger Protein GLI1</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU9P3DAQxS3UChboqffKp16qgJ0_TnyphLYtIK1UJOjZmjiTjavETm1nJT5EvzNeWFF6sUean9_M8yPkI2cXnDN-uYXugtdV0TB5RFa8KmVWlXX9jqxYI1kmCyFPyGkIvxljgglxTE645IUQebkif683t5yaQD1ulxEidjQO3i3bgd5PzsUBLXaZsR3OmA4b6YR6AGvCFKix1KKbRwjRaDqD1R5hX3aLjoGC7RLdmaQa6N23qzXVOI40LH5ndjA-96MHG3rnp_TO2XPyvocx4IfDfUZ-_fj-sL7JNj-vb9dXm0yXtYjJHpZtU-ZNIXLgWqaqqqsWkeea6b6XEnXdyLxs2-S-BWxYB0LXIKTmwHRxRr6-6M5LmzbUyZeHUc3eTOAflQOj_u9YM6it26lcFDkXZRL4fBDw7s-CIarJhL07SB-yBJWzQrKqZgn88gJq70Lw2L8O4Uzt41MpPnWIL9Gf3u71jz3kVTwBs8aaTg</recordid><startdate>20090101</startdate><enddate>20090101</enddate><creator>Nolan-Stevaux, Olivier</creator><creator>Lau, Janet</creator><creator>Truitt, Morgan L</creator><creator>Chu, Gerald C</creator><creator>Hebrok, Matthias</creator><creator>Fernández-Zapico, Martin E</creator><creator>Hanahan, Douglas</creator><general>Cold Spring Harbor Laboratory Press</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20090101</creationdate><title>GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation</title><author>Nolan-Stevaux, Olivier ; Lau, Janet ; Truitt, Morgan L ; Chu, Gerald C ; Hebrok, Matthias ; Fernández-Zapico, Martin E ; Hanahan, Douglas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c476t-54e4b8428362a1c9428575bee12c0cff99ec78924bb936bae80da6c7a69c1a0c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - metabolism</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Cell Line</topic><topic>Cell Survival</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Cells, Cultured</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Hedgehog Proteins - genetics</topic><topic>Hedgehog Proteins - metabolism</topic><topic>Humans</topic><topic>Kruppel-Like Transcription Factors - genetics</topic><topic>Kruppel-Like Transcription Factors - metabolism</topic><topic>Mice</topic><topic>Pancreatic Ducts - metabolism</topic><topic>Pancreatic Ducts - pathology</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Research Paper</topic><topic>Signal Transduction</topic><topic>Smoothened Receptor</topic><topic>Transforming Growth Factor beta - metabolism</topic><topic>Zinc Finger Protein GLI1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nolan-Stevaux, Olivier</creatorcontrib><creatorcontrib>Lau, Janet</creatorcontrib><creatorcontrib>Truitt, Morgan L</creatorcontrib><creatorcontrib>Chu, Gerald C</creatorcontrib><creatorcontrib>Hebrok, Matthias</creatorcontrib><creatorcontrib>Fernández-Zapico, Martin E</creatorcontrib><creatorcontrib>Hanahan, Douglas</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nolan-Stevaux, Olivier</au><au>Lau, Janet</au><au>Truitt, Morgan L</au><au>Chu, Gerald C</au><au>Hebrok, Matthias</au><au>Fernández-Zapico, Martin E</au><au>Hanahan, Douglas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2009-01-01</date><risdate>2009</risdate><volume>23</volume><issue>1</issue><spage>24</spage><epage>36</epage><pages>24-36</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh-Ptch-Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh-Ptch-Smo signaling and is regulated by TGF-beta and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>19136624</pmid><doi>10.1101/gad.1753809</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0890-9369 |
| ispartof | Genes & development, 2009-01, Vol.23 (1), p.24-36 |
| issn | 0890-9369 1549-5477 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2632164 |
| source | PubMed Central Free; MEDLINE; EZB-FREE-00999 freely available EZB journals |
| subjects | Animals Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Cell Line Cell Survival Cell Transformation, Neoplastic - metabolism Cells, Cultured Gene Expression Regulation, Neoplastic Hedgehog Proteins - genetics Hedgehog Proteins - metabolism Humans Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - metabolism Mice Pancreatic Ducts - metabolism Pancreatic Ducts - pathology Pancreatic Neoplasms - genetics Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Proto-Oncogene Proteins p21(ras) - metabolism Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Research Paper Signal Transduction Smoothened Receptor Transforming Growth Factor beta - metabolism Zinc Finger Protein GLI1 |
| title | GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T13%3A42%3A23IST&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=GLI1%20is%20regulated%20through%20Smoothened-independent%20mechanisms%20in%20neoplastic%20pancreatic%20ducts%20and%20mediates%20PDAC%20cell%20survival%20and%20transformation&rft.jtitle=Genes%20&%20development&rft.au=Nolan-Stevaux,%20Olivier&rft.date=2009-01-01&rft.volume=23&rft.issue=1&rft.spage=24&rft.epage=36&rft.pages=24-36&rft.issn=0890-9369&rft.eissn=1549-5477&rft_id=info:doi/10.1101/gad.1753809&rft_dat=%3Cproquest_pubme%3E20390570%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=20390570&rft_id=info:pmid/19136624&rfr_iscdi=true |