A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer
Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated respo...
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| Veröffentlicht in: | The Journal of cell biology 2018-02, Vol.217 (2), p.745-762 |
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| creator | Colaluca, Ivan Nicola Basile, Andrea Freiburger, Lee D'Uva, Veronica Disalvatore, Davide Vecchi, Manuela Confalonieri, Stefano Tosoni, Daniela Cecatiello, Valentina Malabarba, Maria Grazia Yang, Chun-Jiun Kainosho, Masatsune Sattler, Michael Mapelli, Marina Pece, Salvatore Di Fiore, Pier Paolo |
| description | Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment. In this study, we show that the Numb-Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation. Alterations in the Numb splicing pattern are critical in BC as shown by increased chemoresistance of tumors displaying reduced levels of Ex3-containing isoforms, an effect that could be mechanistically linked to diminished p53 levels. A reduced level of Ex3-less Numb isoforms independently predicts poor outcome in BCs harboring wild-type p53. Thus, we have uncovered an important mechanism of chemoresistance and progression in p53-competent BCs. |
| doi_str_mv | 10.1083/jcb.201709092 |
| format | Article |
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This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment. In this study, we show that the Numb-Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation. Alterations in the Numb splicing pattern are critical in BC as shown by increased chemoresistance of tumors displaying reduced levels of Ex3-containing isoforms, an effect that could be mechanistically linked to diminished p53 levels. A reduced level of Ex3-less Numb isoforms independently predicts poor outcome in BCs harboring wild-type p53. Thus, we have uncovered an important mechanism of chemoresistance and progression in p53-competent BCs.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.201709092</identifier><identifier>PMID: 29269425</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Alternative Splicing ; Breast cancer ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Cell Line, Tumor ; Chemoresistance ; Degradation ; Female ; Fuzzy logic ; Genotoxicity ; Homeostasis ; Humans ; Isoforms ; MDM2 protein ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Notch protein ; NUMB protein ; p53 Protein ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Proto-Oncogene Proteins c-mdm2 - genetics ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Signaling ; Splicing ; Stem cells ; Toxicity ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Ubiquitin-protein ligase</subject><ispartof>The Journal of cell biology, 2018-02, Vol.217 (2), p.745-762</ispartof><rights>2018 Colaluca et al.</rights><rights>Copyright Rockefeller University Press Feb 2018</rights><rights>2018 Colaluca et al. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-8747db77efe31e1b8c0dcd64085cd1f299bec61e4b6f4df90b4a03dcd9db0c583</citedby><cites>FETCH-LOGICAL-c411t-8747db77efe31e1b8c0dcd64085cd1f299bec61e4b6f4df90b4a03dcd9db0c583</cites><orcidid>0000-0002-1594-0527 ; 0000-0002-2252-0950 ; 0000-0001-6886-9851 ; 0000-0002-3371-112X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29269425$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Colaluca, Ivan Nicola</creatorcontrib><creatorcontrib>Basile, Andrea</creatorcontrib><creatorcontrib>Freiburger, Lee</creatorcontrib><creatorcontrib>D'Uva, Veronica</creatorcontrib><creatorcontrib>Disalvatore, Davide</creatorcontrib><creatorcontrib>Vecchi, Manuela</creatorcontrib><creatorcontrib>Confalonieri, Stefano</creatorcontrib><creatorcontrib>Tosoni, Daniela</creatorcontrib><creatorcontrib>Cecatiello, Valentina</creatorcontrib><creatorcontrib>Malabarba, Maria Grazia</creatorcontrib><creatorcontrib>Yang, Chun-Jiun</creatorcontrib><creatorcontrib>Kainosho, Masatsune</creatorcontrib><creatorcontrib>Sattler, Michael</creatorcontrib><creatorcontrib>Mapelli, Marina</creatorcontrib><creatorcontrib>Pece, Salvatore</creatorcontrib><creatorcontrib>Di Fiore, Pier Paolo</creatorcontrib><title>A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment. In this study, we show that the Numb-Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation. Alterations in the Numb splicing pattern are critical in BC as shown by increased chemoresistance of tumors displaying reduced levels of Ex3-containing isoforms, an effect that could be mechanistically linked to diminished p53 levels. A reduced level of Ex3-less Numb isoforms independently predicts poor outcome in BCs harboring wild-type p53. Thus, we have uncovered an important mechanism of chemoresistance and progression in p53-competent BCs.</description><subject>Alternative Splicing</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Chemoresistance</subject><subject>Degradation</subject><subject>Female</subject><subject>Fuzzy logic</subject><subject>Genotoxicity</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Isoforms</subject><subject>MDM2 protein</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Notch protein</subject><subject>NUMB protein</subject><subject>p53 Protein</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2 - genetics</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Signaling</subject><subject>Splicing</subject><subject>Stem cells</subject><subject>Toxicity</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>Ubiquitin-protein ligase</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1v1DAQhi0EokvpkSuy1AuXlBnHieNLpariSyrtBS69WLYzhqySeGtvVrS_HpeWVeE00swzj2b0MvYG4QShq9-vvTsRgAo0aPGMrbCRUHUo4TlbAQisdCOaA_Yq5zUASCXrl-xAaNFqKZoVuz7jl8vkqq_9JHhY7u5uuY_TZqRfPNGO7Ji5nfmQY4hpqvKG_BAGz4d5F8cdTTRveQx_FKXHXSKbt9zb2VN6zV6Esk9Hj_WQff_44dv55-ri6tOX87OLykvEbdUpqXqnFAWqkdB1HnrftxK6xvcYhNaOfIskXRtkHzQ4aaEuiO4d-KarD9npg3ezuIl6X25KdjSbNEw23ZpoB_PvZB5-mh9xZ5oOoMN7wbtHQYo3C-WtmYbsaRztTHHJBrXSulUC6oIe_4eu45Lm8p4RRVY3KBQWqnqgfIo5Jwr7YxDMfWqmpGb2qRX-7dMP9vTfmOrfoSOURA</recordid><startdate>20180205</startdate><enddate>20180205</enddate><creator>Colaluca, Ivan Nicola</creator><creator>Basile, Andrea</creator><creator>Freiburger, Lee</creator><creator>D'Uva, Veronica</creator><creator>Disalvatore, Davide</creator><creator>Vecchi, Manuela</creator><creator>Confalonieri, Stefano</creator><creator>Tosoni, Daniela</creator><creator>Cecatiello, Valentina</creator><creator>Malabarba, Maria Grazia</creator><creator>Yang, Chun-Jiun</creator><creator>Kainosho, Masatsune</creator><creator>Sattler, Michael</creator><creator>Mapelli, Marina</creator><creator>Pece, Salvatore</creator><creator>Di Fiore, Pier Paolo</creator><general>Rockefeller University Press</general><general>The Rockefeller University 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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</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><orcidid>https://orcid.org/0000-0002-1594-0527</orcidid><orcidid>https://orcid.org/0000-0002-2252-0950</orcidid><orcidid>https://orcid.org/0000-0001-6886-9851</orcidid><orcidid>https://orcid.org/0000-0002-3371-112X</orcidid></search><sort><creationdate>20180205</creationdate><title>A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer</title><author>Colaluca, Ivan Nicola ; Basile, Andrea ; Freiburger, Lee ; D'Uva, Veronica ; Disalvatore, Davide ; Vecchi, Manuela ; Confalonieri, Stefano ; Tosoni, Daniela ; Cecatiello, Valentina ; Malabarba, Maria Grazia ; Yang, Chun-Jiun ; Kainosho, Masatsune ; Sattler, Michael ; Mapelli, Marina ; Pece, Salvatore ; Di Fiore, Pier Paolo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c411t-8747db77efe31e1b8c0dcd64085cd1f299bec61e4b6f4df90b4a03dcd9db0c583</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Alternative Splicing</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Chemoresistance</topic><topic>Degradation</topic><topic>Female</topic><topic>Fuzzy logic</topic><topic>Genotoxicity</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Isoforms</topic><topic>MDM2 protein</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Nerve Tissue Proteins - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Notch protein</topic><topic>NUMB protein</topic><topic>p53 Protein</topic><topic>Protein Isoforms - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2 - genetics</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Signaling</topic><topic>Splicing</topic><topic>Stem cells</topic><topic>Toxicity</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><topic>Ubiquitin-protein ligase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Colaluca, Ivan Nicola</creatorcontrib><creatorcontrib>Basile, Andrea</creatorcontrib><creatorcontrib>Freiburger, Lee</creatorcontrib><creatorcontrib>D'Uva, Veronica</creatorcontrib><creatorcontrib>Disalvatore, Davide</creatorcontrib><creatorcontrib>Vecchi, Manuela</creatorcontrib><creatorcontrib>Confalonieri, Stefano</creatorcontrib><creatorcontrib>Tosoni, Daniela</creatorcontrib><creatorcontrib>Cecatiello, Valentina</creatorcontrib><creatorcontrib>Malabarba, Maria Grazia</creatorcontrib><creatorcontrib>Yang, Chun-Jiun</creatorcontrib><creatorcontrib>Kainosho, Masatsune</creatorcontrib><creatorcontrib>Sattler, Michael</creatorcontrib><creatorcontrib>Mapelli, Marina</creatorcontrib><creatorcontrib>Pece, Salvatore</creatorcontrib><creatorcontrib>Di Fiore, Pier Paolo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids 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>The Journal of cell biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Colaluca, Ivan Nicola</au><au>Basile, Andrea</au><au>Freiburger, Lee</au><au>D'Uva, Veronica</au><au>Disalvatore, Davide</au><au>Vecchi, Manuela</au><au>Confalonieri, Stefano</au><au>Tosoni, Daniela</au><au>Cecatiello, Valentina</au><au>Malabarba, Maria Grazia</au><au>Yang, Chun-Jiun</au><au>Kainosho, Masatsune</au><au>Sattler, Michael</au><au>Mapelli, Marina</au><au>Pece, Salvatore</au><au>Di Fiore, Pier Paolo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2018-02-05</date><risdate>2018</risdate><volume>217</volume><issue>2</issue><spage>745</spage><epage>762</epage><pages>745-762</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><abstract>Numb functions as an oncosuppressor by inhibiting Notch signaling and stabilizing p53. This latter effect depends on the interaction of Numb with Mdm2, the E3 ligase that ubiquitinates p53 and commits it to degradation. In breast cancer (BC), loss of Numb results in a reduction of p53-mediated responses including sensitivity to genotoxic drugs and maintenance of homeostasis in the stem cell compartment. In this study, we show that the Numb-Mdm2 interaction represents a fuzzy complex mediated by a short Numb sequence encompassing its alternatively spliced exon 3 (Ex3), which is necessary and sufficient to inhibit Mdm2 and prevent p53 degradation. Alterations in the Numb splicing pattern are critical in BC as shown by increased chemoresistance of tumors displaying reduced levels of Ex3-containing isoforms, an effect that could be mechanistically linked to diminished p53 levels. A reduced level of Ex3-less Numb isoforms independently predicts poor outcome in BCs harboring wild-type p53. Thus, we have uncovered an important mechanism of chemoresistance and progression in p53-competent BCs.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>29269425</pmid><doi>10.1083/jcb.201709092</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-1594-0527</orcidid><orcidid>https://orcid.org/0000-0002-2252-0950</orcidid><orcidid>https://orcid.org/0000-0001-6886-9851</orcidid><orcidid>https://orcid.org/0000-0002-3371-112X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alternative Splicing Breast cancer Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer Cell Line, Tumor Chemoresistance Degradation Female Fuzzy logic Genotoxicity Homeostasis Humans Isoforms MDM2 protein Membrane Proteins - genetics Membrane Proteins - metabolism Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Notch protein NUMB protein p53 Protein Protein Isoforms - genetics Protein Isoforms - metabolism Proto-Oncogene Proteins c-mdm2 - genetics Proto-Oncogene Proteins c-mdm2 - metabolism Signaling Splicing Stem cells Toxicity Tumor Suppressor Protein p53 - metabolism Tumors Ubiquitin-protein ligase |
| title | A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer |
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