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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800818/ https://www.ncbi.nlm.nih.gov/pubmed/29269425 http://dx.doi.org/10.1083/jcb.201709092 |
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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_facet | 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 | Colaluca, Ivan Nicola |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-5800818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-58008182018-02-07 A Numb–Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer 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 J Cell Biol Research Articles 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. The Rockefeller University Press 2018-02-05 /pmc/articles/PMC5800818/ /pubmed/29269425 http://dx.doi.org/10.1083/jcb.201709092 Text en © 2018 Colaluca et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles 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 A Numb–Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer |
title | A Numb–Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer |
title_full | A Numb–Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer |
title_fullStr | A Numb–Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer |
title_full_unstemmed | A Numb–Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer |
title_short | A Numb–Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer |
title_sort | numb–mdm2 fuzzy complex reveals an isoform-specific involvement of numb in breast cancer |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800818/ https://www.ncbi.nlm.nih.gov/pubmed/29269425 http://dx.doi.org/10.1083/jcb.201709092 |
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