Ras Activity Regulates Cyclin E Degradation by the Fbw7 Pathway
The Skp1-Cullin 1 F-box protein-Fbw7 ubiquitin ligase regulates phosphorylation-dependent cyclin E degradation, and disruption of this pathway is associated with genetic instability and tumorigenesis. Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechani...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-07, Vol.102 (27), p.9649-9654 |
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| creator | Minella, Alex C. Welcker, Markus Clurman, Bruce E. Hartwell, Leland H. |
| description | The Skp1-Cullin 1 F-box protein-Fbw7 ubiquitin ligase regulates phosphorylation-dependent cyclin E degradation, and disruption of this pathway is associated with genetic instability and tumorigenesis. Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechanisms other than mutation of Fbw7 may also disrupt cyclin E proteolysis in cancers. We show that oncogenic Ha-Ras activity regulates cyclin E degradation by the Fbw7 pathway. Activated Ras impairs Fbw7-driven cyclin E degradation, and, conversely, inhibition of normal Ras activity decreases cyclin E abundance. Moreover, activation of the mitogen-activated protein kinase pathway is the essential Ras function that inhibits cyclin E turnover, and activated Ha-Ras expression inhibits both the binding of cyclin E to Fbw7 and cyclin E ubiquitination. Last, we found that oncogenic Ras activity potentiates cyclin E-induced genetic instability but only when cyclin E is susceptible to degradation by Fbw7. Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis. |
| doi_str_mv | 10.1073/pnas.0503677102 |
| format | Article |
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Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechanisms other than mutation of Fbw7 may also disrupt cyclin E proteolysis in cancers. We show that oncogenic Ha-Ras activity regulates cyclin E degradation by the Fbw7 pathway. Activated Ras impairs Fbw7-driven cyclin E degradation, and, conversely, inhibition of normal Ras activity decreases cyclin E abundance. Moreover, activation of the mitogen-activated protein kinase pathway is the essential Ras function that inhibits cyclin E turnover, and activated Ha-Ras expression inhibits both the binding of cyclin E to Fbw7 and cyclin E ubiquitination. Last, we found that oncogenic Ras activity potentiates cyclin E-induced genetic instability but only when cyclin E is susceptible to degradation by Fbw7. Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0503677102</identifier><identifier>PMID: 15980150</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>3T3 cells ; Animals ; Biological Sciences ; Cancer ; Cell Cycle Proteins - metabolism ; Cells ; Cyclin E - metabolism ; Cyclins ; F-Box Proteins - metabolism ; F-Box-WD Repeat-Containing Protein 7 ; Fibroblasts ; Gene expression regulation ; HeLa Cells ; Human genetics ; Humans ; Immunoblotting ; Immunoprecipitation ; Mice ; Micronucleus Tests ; Microscopy, Fluorescence ; Mutation ; NIH 3T3 Cells ; Phosphorylation ; Plasmids ; Polymerase Chain Reaction ; Proteins ; Proto-Oncogene Proteins p21(ras) - metabolism ; Signal Transduction - physiology ; Tumors ; Ubiquitin-Protein Ligases - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2005-07, Vol.102 (27), p.9649-9654</ispartof><rights>Copyright 1993/2005 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jul 5, 2005</rights><rights>Copyright © 2005, The National Academy of Sciences 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c527t-f5a1c1d34e7d2c6307e7ad783fd7fb7155f380c473efc87415812fd6f5c3794d3</citedby><cites>FETCH-LOGICAL-c527t-f5a1c1d34e7d2c6307e7ad783fd7fb7155f380c473efc87415812fd6f5c3794d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/102/27.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/3376028$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/3376028$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15980150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Minella, Alex C.</creatorcontrib><creatorcontrib>Welcker, Markus</creatorcontrib><creatorcontrib>Clurman, Bruce E.</creatorcontrib><creatorcontrib>Hartwell, Leland H.</creatorcontrib><title>Ras Activity Regulates Cyclin E Degradation by the Fbw7 Pathway</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The Skp1-Cullin 1 F-box protein-Fbw7 ubiquitin ligase regulates phosphorylation-dependent cyclin E degradation, and disruption of this pathway is associated with genetic instability and tumorigenesis. Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechanisms other than mutation of Fbw7 may also disrupt cyclin E proteolysis in cancers. We show that oncogenic Ha-Ras activity regulates cyclin E degradation by the Fbw7 pathway. Activated Ras impairs Fbw7-driven cyclin E degradation, and, conversely, inhibition of normal Ras activity decreases cyclin E abundance. Moreover, activation of the mitogen-activated protein kinase pathway is the essential Ras function that inhibits cyclin E turnover, and activated Ha-Ras expression inhibits both the binding of cyclin E to Fbw7 and cyclin E ubiquitination. Last, we found that oncogenic Ras activity potentiates cyclin E-induced genetic instability but only when cyclin E is susceptible to degradation by Fbw7. Thus, we conclude that Ras activity regulates Fbw7-mediated cyclin E proteolysis and suggest that impaired cyclin E proteolysis is a mechanism through which Ras mutations promote tumorigenesis.</description><subject>3T3 cells</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Cancer</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cells</subject><subject>Cyclin E - metabolism</subject><subject>Cyclins</subject><subject>F-Box Proteins - metabolism</subject><subject>F-Box-WD Repeat-Containing Protein 7</subject><subject>Fibroblasts</subject><subject>Gene expression regulation</subject><subject>HeLa Cells</subject><subject>Human genetics</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Immunoprecipitation</subject><subject>Mice</subject><subject>Micronucleus Tests</subject><subject>Microscopy, Fluorescence</subject><subject>Mutation</subject><subject>NIH 3T3 Cells</subject><subject>Phosphorylation</subject><subject>Plasmids</subject><subject>Polymerase Chain Reaction</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>Tumors</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c9v0zAUB3ALgVgZnLkgsDggLtnes-M85wKaygZIk0ATnC3XsdtUaVJiZyP_PalarcABTj74877-8WXsOcIZAsnzbWvjGSiQBRGCeMBmCCVmRV7CQzYDEJTpXOQn7EmMawAolYbH7ARVqQEVzNj7Gxv5hUv1bZ1GfuOXQ2OTj3w-uqZu-SX_4Je9rWyqu5YvRp5Wnl8t7oh_tWl1Z8en7FGwTfTPDusp-351-W3-Kbv-8vHz_OI6c0pQyoKy6LCSuadKuEICebIVaRkqCgtCpYLU4HKSPjhNOSqNIlRFUE5SmVfylL3b526HxcZXzrept43Z9vXG9qPpbG3-3GnrlVl2twaRhCjkFPDmENB3PwYfk9nU0fmmsa3vhmgKDZAD4n8hUpHrPXz9F1x3Q99Ov2AEoJzOhGJC53vk-i7G3of7KyOYXYVmV6E5VjhNvPz9pUd_6GwCbw9gN3mME0aQKafqTRiaJvmfaaKv_k0n8WIv1jF1_T2RkgoQWv4CY--3sQ</recordid><startdate>20050705</startdate><enddate>20050705</enddate><creator>Minella, Alex C.</creator><creator>Welcker, Markus</creator><creator>Clurman, Bruce E.</creator><creator>Hartwell, Leland H.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20050705</creationdate><title>Ras Activity Regulates Cyclin E Degradation by the Fbw7 Pathway</title><author>Minella, Alex C. ; Welcker, Markus ; Clurman, Bruce E. ; Hartwell, Leland H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c527t-f5a1c1d34e7d2c6307e7ad783fd7fb7155f380c473efc87415812fd6f5c3794d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>3T3 cells</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>Cancer</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cells</topic><topic>Cyclin E - metabolism</topic><topic>Cyclins</topic><topic>F-Box Proteins - metabolism</topic><topic>F-Box-WD Repeat-Containing Protein 7</topic><topic>Fibroblasts</topic><topic>Gene expression regulation</topic><topic>HeLa Cells</topic><topic>Human genetics</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Immunoprecipitation</topic><topic>Mice</topic><topic>Micronucleus Tests</topic><topic>Microscopy, Fluorescence</topic><topic>Mutation</topic><topic>NIH 3T3 Cells</topic><topic>Phosphorylation</topic><topic>Plasmids</topic><topic>Polymerase Chain Reaction</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>Tumors</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Minella, Alex C.</creatorcontrib><creatorcontrib>Welcker, Markus</creatorcontrib><creatorcontrib>Clurman, Bruce E.</creatorcontrib><creatorcontrib>Hartwell, Leland H.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Minella, Alex C.</au><au>Welcker, Markus</au><au>Clurman, Bruce E.</au><au>Hartwell, Leland H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ras Activity Regulates Cyclin E Degradation by the Fbw7 Pathway</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2005-07-05</date><risdate>2005</risdate><volume>102</volume><issue>27</issue><spage>9649</spage><epage>9654</epage><pages>9649-9654</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The Skp1-Cullin 1 F-box protein-Fbw7 ubiquitin ligase regulates phosphorylation-dependent cyclin E degradation, and disruption of this pathway is associated with genetic instability and tumorigenesis. Fbw7 is a human tumor suppressor that is targeted for mutation in primary cancers. However, mechanisms other than mutation of Fbw7 may also disrupt cyclin E proteolysis in cancers. We show that oncogenic Ha-Ras activity regulates cyclin E degradation by the Fbw7 pathway. Activated Ras impairs Fbw7-driven cyclin E degradation, and, conversely, inhibition of normal Ras activity decreases cyclin E abundance. Moreover, activation of the mitogen-activated protein kinase pathway is the essential Ras function that inhibits cyclin E turnover, and activated Ha-Ras expression inhibits both the binding of cyclin E to Fbw7 and cyclin E ubiquitination. Last, we found that oncogenic Ras activity potentiates cyclin E-induced genetic instability but only when cyclin E is susceptible to degradation by Fbw7. 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| subjects | 3T3 cells Animals Biological Sciences Cancer Cell Cycle Proteins - metabolism Cells Cyclin E - metabolism Cyclins F-Box Proteins - metabolism F-Box-WD Repeat-Containing Protein 7 Fibroblasts Gene expression regulation HeLa Cells Human genetics Humans Immunoblotting Immunoprecipitation Mice Micronucleus Tests Microscopy, Fluorescence Mutation NIH 3T3 Cells Phosphorylation Plasmids Polymerase Chain Reaction Proteins Proto-Oncogene Proteins p21(ras) - metabolism Signal Transduction - physiology Tumors Ubiquitin-Protein Ligases - metabolism |
| title | Ras Activity Regulates Cyclin E Degradation by the Fbw7 Pathway |
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