Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/172125
Title: | Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis |
Author: | Li, Li Guturi, Kiran Kumar Naidu Gautreau, Brandon Patel, Parasvi S. Saad, Amine Morii, Mayako Mateo González, Francesca Palomero, Luis Barbour, Haithem Gomez, Antonio Ng, Deborah Kotlyar, Max Pastrello, Chiara Jackson, Hartland W. Khokha, Rama Jurisica, Igor Affar, El Bachir Raught, Brian Sanchez, Otto Alaoui-Jmali, Moulay Pujana Genestar, M. Ángel Hakem, Anne Hakem, Razq |
Keywords: | Ubiqüitina Reparació de l'ADN Ubiquitin DNA repair |
Issue Date: | 1-Oct-2018 |
Publisher: | American Society Clinical Investigation Inc. |
Abstract: | The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(AOP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function. |
Note: | Reproducció del document publicat a: https://doi.org/10.1172/JCI120401 |
It is part of: | Journal of Clinical Investigation, 2018, vol. 128, num. 10, p. 4525-4542 |
URI: | http://hdl.handle.net/2445/172125 |
Related resource: | https://doi.org/10.1172/JCI120401 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.