Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2018
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
_version_ 1783298261683011584
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
work_keys_str_mv AT colalucaivannicola anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT basileandrea anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT freiburgerlee anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT duvaveronica anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT disalvatoredavide anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT vecchimanuela anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT confalonieristefano anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT tosonidaniela anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT cecatiellovalentina anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT malabarbamariagrazia anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT yangchunjiun anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT kainoshomasatsune anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT sattlermichael anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT mapellimarina anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT pecesalvatore anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT difiorepierpaolo anumbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT colalucaivannicola numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT basileandrea numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT freiburgerlee numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT duvaveronica numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT disalvatoredavide numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT vecchimanuela numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT confalonieristefano numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT tosonidaniela numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT cecatiellovalentina numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT malabarbamariagrazia numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT yangchunjiun numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT kainoshomasatsune numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT sattlermichael numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT mapellimarina numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT pecesalvatore numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer
AT difiorepierpaolo numbmdm2fuzzycomplexrevealsanisoformspecificinvolvementofnumbinbreastcancer