Miniatura

Fitxers

LiL.pdf (21.29 MB)

Tipus de document

Article

Versió

Versió publicada

Data de publicació

2018-10-01

Tots els drets reservats

Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/172125

Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis

Títol de la revista

Autors

Director/Tutor

ISSN de la revista

Títol del volum

Recurs relacionat

https://doi.org/10.1172/JCI120401

Resum

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.

Matèries

Ubiqüitina, Reparació de l'ADN

Matèries (anglès)

Ubiquitin, DNA repair

Citació

Col·leccions

Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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. Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis. _Journal of Clinical Investigation_. 2018. Vol. 128, núm. 10, pàgs. 4525-4542. [consulta: 31 de gener de 2026]. [Disponible a: https://hdl.handle.net/2445/172125]

Exportar metadades

JSON - METS

Compartir registre