A Numb-Mdm2 fuzzy complex reveals an isoformspecific involvement of Numb in breast cancer

Ivan Nicola Colaluca, Andrea Basile, Lee Freiburger, Veronica D'Uva, Davide Disalvatore, Manuela Vecchi, Stefano Confalonieri, Daniela Tosoni, Valentina Cecatiello, Maria Grazia Malabarba, Chun Jiun Yang, Masatsune Kainosho, Michael Sattler, Marina Mapelli, Salvatore Pece, Pier Paolo di Fiore

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)745-762
Number of pages18
JournalJournal of Cell Biology
Volume217
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

ASJC Scopus subject areas

  • Cell Biology

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    Colaluca, I. N., Basile, A., Freiburger, L., D'Uva, V., Disalvatore, D., Vecchi, M., Confalonieri, S., Tosoni, D., Cecatiello, V., Malabarba, M. G., Yang, C. J., Kainosho, M., Sattler, M., Mapelli, M., Pece, S., & di Fiore, P. P. (2018). A Numb-Mdm2 fuzzy complex reveals an isoformspecific involvement of Numb in breast cancer. Journal of Cell Biology, 217(2), 745-762. https://doi.org/10.1083/jcb.201709092