The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma
Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau ( VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the α subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic c...
Gespeichert in:
| Veröffentlicht in: | Cancer cell 2002-04, Vol.1 (3), p.247-255 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 255 |
|---|---|
| container_issue | 3 |
| container_start_page | 247 |
| container_title | Cancer cell |
| container_volume | 1 |
| creator | Maranchie, Jodi K Vasselli, James R Riss, Joseph Bonifacino, Juan S Linehan, W.Marston Klausner, Richard D |
| description | Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (
VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the α subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1α recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1α alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL. |
| doi_str_mv | 10.1016/S1535-6108(02)00044-2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_71858163</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1535610802000442</els_id><sourcerecordid>71858163</sourcerecordid><originalsourceid>FETCH-LOGICAL-c491t-f8bd498d981f9ddd4ab9f24df9dc9c9fa9bbdd4701f59bcd179f23a6642d8dd63</originalsourceid><addsrcrecordid>eNqFkctOGzEUhi3UqlzaR6DyqqKLKT4ez8ReIYQKQYrEAujW8rUYJXawPUg8Vl-kz1SHBHXJxjd9_zk-_4_QMZAfQGA8vYWhH7oRCD8h9DshhLGO7qED4DPe9SMfP7TzG7KPDkt5JE0HM_EJ7QMlvCFwgB7vHhw2KdYc9FRDijh5_Gu-wGXSpWZVHdYh2hB_YxUtnl9fQvf3D64J1yZcP7iY6svavamWqRQcIs4uqiU2btkWlU2IaaU-o49eLYv7stuP0P3lz7uLebe4ubq-OF90hgmonefaMsGt4OCFtZYpLTxltl2MMMIroXV7nRHwg9DGtok87dU4Mmq5tWN_hL5t665zeppcqXIVyuYrKro0FTkDPnAY-3dB4L1gjG4qDlvQ5DZfdl6uc1ip_CKByE0a8jUNubFaEipf05C06b7uGkx65ex_1c7-BpxtAdf8eA4uy2KCi8bZkJ2p0qbwTot_Q8Caqg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>18394426</pqid></control><display><type>article</type><title>The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma</title><source>MEDLINE</source><source>Cell Press Archives</source><source>Elsevier ScienceDirect Journals Complete</source><source>EZB Electronic Journals Library</source><creator>Maranchie, Jodi K ; Vasselli, James R ; Riss, Joseph ; Bonifacino, Juan S ; Linehan, W.Marston ; Klausner, Richard D</creator><creatorcontrib>Maranchie, Jodi K ; Vasselli, James R ; Riss, Joseph ; Bonifacino, Juan S ; Linehan, W.Marston ; Klausner, Richard D</creatorcontrib><description>Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (
VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the α subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1α recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1α alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/S1535-6108(02)00044-2</identifier><identifier>PMID: 12086861</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Binding Sites ; Blotting, Western ; Carcinoma, Renal Cell - genetics ; Carcinoma, Renal Cell - metabolism ; Carcinoma, Renal Cell - pathology ; Female ; Genes, Tumor Suppressor ; Glucose Transporter Type 1 ; Green Fluorescent Proteins ; HeLa Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; Immunoenzyme Techniques ; Kidney Neoplasms - genetics ; Kidney Neoplasms - metabolism ; Kidney Neoplasms - pathology ; Ligases - metabolism ; Luciferases - metabolism ; Luminescent Proteins - metabolism ; Mice ; Mice, SCID ; Monosaccharide Transport Proteins - metabolism ; Phenotype ; Plasmids ; Recombinant Fusion Proteins ; Transcription Factors - metabolism ; Transcription, Genetic ; Transfection ; Tumor Suppressor Proteins ; Ubiquitin-Protein Ligases ; Von Hippel-Lindau Tumor Suppressor Protein</subject><ispartof>Cancer cell, 2002-04, Vol.1 (3), p.247-255</ispartof><rights>2002 Cell Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c491t-f8bd498d981f9ddd4ab9f24df9dc9c9fa9bbdd4701f59bcd179f23a6642d8dd63</citedby><cites>FETCH-LOGICAL-c491t-f8bd498d981f9ddd4ab9f24df9dc9c9fa9bbdd4701f59bcd179f23a6642d8dd63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610802000442$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12086861$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maranchie, Jodi K</creatorcontrib><creatorcontrib>Vasselli, James R</creatorcontrib><creatorcontrib>Riss, Joseph</creatorcontrib><creatorcontrib>Bonifacino, Juan S</creatorcontrib><creatorcontrib>Linehan, W.Marston</creatorcontrib><creatorcontrib>Klausner, Richard D</creatorcontrib><title>The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (
VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the α subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1α recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1α alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Blotting, Western</subject><subject>Carcinoma, Renal Cell - genetics</subject><subject>Carcinoma, Renal Cell - metabolism</subject><subject>Carcinoma, Renal Cell - pathology</subject><subject>Female</subject><subject>Genes, Tumor Suppressor</subject><subject>Glucose Transporter Type 1</subject><subject>Green Fluorescent Proteins</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit</subject><subject>Immunoenzyme Techniques</subject><subject>Kidney Neoplasms - genetics</subject><subject>Kidney Neoplasms - metabolism</subject><subject>Kidney Neoplasms - pathology</subject><subject>Ligases - metabolism</subject><subject>Luciferases - metabolism</subject><subject>Luminescent Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Monosaccharide Transport Proteins - metabolism</subject><subject>Phenotype</subject><subject>Plasmids</subject><subject>Recombinant Fusion Proteins</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic</subject><subject>Transfection</subject><subject>Tumor Suppressor Proteins</subject><subject>Ubiquitin-Protein Ligases</subject><subject>Von Hippel-Lindau Tumor Suppressor Protein</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctOGzEUhi3UqlzaR6DyqqKLKT4ez8ReIYQKQYrEAujW8rUYJXawPUg8Vl-kz1SHBHXJxjd9_zk-_4_QMZAfQGA8vYWhH7oRCD8h9DshhLGO7qED4DPe9SMfP7TzG7KPDkt5JE0HM_EJ7QMlvCFwgB7vHhw2KdYc9FRDijh5_Gu-wGXSpWZVHdYh2hB_YxUtnl9fQvf3D64J1yZcP7iY6svavamWqRQcIs4uqiU2btkWlU2IaaU-o49eLYv7stuP0P3lz7uLebe4ubq-OF90hgmonefaMsGt4OCFtZYpLTxltl2MMMIroXV7nRHwg9DGtok87dU4Mmq5tWN_hL5t665zeppcqXIVyuYrKro0FTkDPnAY-3dB4L1gjG4qDlvQ5DZfdl6uc1ip_CKByE0a8jUNubFaEipf05C06b7uGkx65ex_1c7-BpxtAdf8eA4uy2KCi8bZkJ2p0qbwTot_Q8Caqg</recordid><startdate>20020401</startdate><enddate>20020401</enddate><creator>Maranchie, Jodi K</creator><creator>Vasselli, James R</creator><creator>Riss, Joseph</creator><creator>Bonifacino, Juan S</creator><creator>Linehan, W.Marston</creator><creator>Klausner, Richard D</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20020401</creationdate><title>The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma</title><author>Maranchie, Jodi K ; Vasselli, James R ; Riss, Joseph ; Bonifacino, Juan S ; Linehan, W.Marston ; Klausner, Richard D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c491t-f8bd498d981f9ddd4ab9f24df9dc9c9fa9bbdd4701f59bcd179f23a6642d8dd63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Binding Sites</topic><topic>Blotting, Western</topic><topic>Carcinoma, Renal Cell - genetics</topic><topic>Carcinoma, Renal Cell - metabolism</topic><topic>Carcinoma, Renal Cell - pathology</topic><topic>Female</topic><topic>Genes, Tumor Suppressor</topic><topic>Glucose Transporter Type 1</topic><topic>Green Fluorescent Proteins</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit</topic><topic>Immunoenzyme Techniques</topic><topic>Kidney Neoplasms - genetics</topic><topic>Kidney Neoplasms - metabolism</topic><topic>Kidney Neoplasms - pathology</topic><topic>Ligases - metabolism</topic><topic>Luciferases - metabolism</topic><topic>Luminescent Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Monosaccharide Transport Proteins - metabolism</topic><topic>Phenotype</topic><topic>Plasmids</topic><topic>Recombinant Fusion Proteins</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic</topic><topic>Transfection</topic><topic>Tumor Suppressor Proteins</topic><topic>Ubiquitin-Protein Ligases</topic><topic>Von Hippel-Lindau Tumor Suppressor Protein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maranchie, Jodi K</creatorcontrib><creatorcontrib>Vasselli, James R</creatorcontrib><creatorcontrib>Riss, Joseph</creatorcontrib><creatorcontrib>Bonifacino, Juan S</creatorcontrib><creatorcontrib>Linehan, W.Marston</creatorcontrib><creatorcontrib>Klausner, Richard D</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maranchie, Jodi K</au><au>Vasselli, James R</au><au>Riss, Joseph</au><au>Bonifacino, Juan S</au><au>Linehan, W.Marston</au><au>Klausner, Richard D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2002-04-01</date><risdate>2002</risdate><volume>1</volume><issue>3</issue><spage>247</spage><epage>255</epage><pages>247-255</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Clear-cell renal carcinoma is associated with inactivation of the von Hippel-Lindau (
VHL) tumor suppressor gene. VHL is the substrate recognition subunit of an E3 ligase, known to target the α subunits of the HIF heterodimeric transcription factor for ubiquitin-mediated degradation under normoxic conditions. We demonstrate that competitive inhibition of the VHL substrate recognition site with a peptide derived from the oxygen degradation domain of HIF1α recapitulates the tumorigenic phenotype of VHL-deficient tumor cells. These studies prove that VHL substrate recognition is essential to the tumor suppressor function of VHL. We further demonstrate that normoxic stabilization of HIF1α alone, while capable of mimicking some aspects of VHL loss, is not sufficient to reproduce tumorigenesis, indicating that it is not the critical oncogenic substrate of VHL.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>12086861</pmid><doi>10.1016/S1535-6108(02)00044-2</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1535-6108 |
| ispartof | Cancer cell, 2002-04, Vol.1 (3), p.247-255 |
| issn | 1535-6108 1878-3686 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_71858163 |
| source | MEDLINE; Cell Press Archives; Elsevier ScienceDirect Journals Complete; EZB Electronic Journals Library |
| subjects | Animals Binding Sites Blotting, Western Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - metabolism Carcinoma, Renal Cell - pathology Female Genes, Tumor Suppressor Glucose Transporter Type 1 Green Fluorescent Proteins HeLa Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit Immunoenzyme Techniques Kidney Neoplasms - genetics Kidney Neoplasms - metabolism Kidney Neoplasms - pathology Ligases - metabolism Luciferases - metabolism Luminescent Proteins - metabolism Mice Mice, SCID Monosaccharide Transport Proteins - metabolism Phenotype Plasmids Recombinant Fusion Proteins Transcription Factors - metabolism Transcription, Genetic Transfection Tumor Suppressor Proteins Ubiquitin-Protein Ligases Von Hippel-Lindau Tumor Suppressor Protein |
| title | The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-14T17%3A24%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20contribution%20of%20VHL%20substrate%20binding%20and%20HIF1-%CE%B1%20to%20the%20phenotype%20of%20VHL%20loss%20in%20renal%20cell%20carcinoma&rft.jtitle=Cancer%20cell&rft.au=Maranchie,%20Jodi%20K&rft.date=2002-04-01&rft.volume=1&rft.issue=3&rft.spage=247&rft.epage=255&rft.pages=247-255&rft.issn=1535-6108&rft.eissn=1878-3686&rft_id=info:doi/10.1016/S1535-6108(02)00044-2&rft_dat=%3Cproquest_cross%3E71858163%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=18394426&rft_id=info:pmid/12086861&rft_els_id=S1535610802000442&rfr_iscdi=true |