p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating with the Notch Transcriptional Complex via MAML1 Journal Article

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Authors: Yun, J; Espinoza, I.; Pannuti, A.; Romero, D.; Martinez, L.; Caskey, M.; Stanculescu, A.; Bocchetta, M; Rizzo, P.; Band, V.; Band, H.; Kim, H. M.; Park, S. K.; Kang, K. W.; Avantaggiati, M. L.; Gomez, C. R.; Golde, T.; Osborne, B.; Miele, L
Article Title: p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating with the Notch Transcriptional Complex via MAML1
Abstract: p53 and Notch-1 play important roles in breast cancer biology. Notch-1 inhibits p53 activity in cervical and breast cancer cells. Conversely, p53 inhibits Notch activity in T-cells but stimulates it in human keratinocytes. Notch co-activator MAML1 binds p53 and functions as a p53 co-activator. We studied the regulation of Notch signaling by p53 in MCF-7 cells and normal human mammary epithelial cells (HMEC). Results show that overexpression of p53 or activation of endogenous p53 with Nutlin-3 inhibits Notch-dependent transcriptional activity and Notch target expression in a dose-dependent manner. This effect could be partially rescued by transfection of MAML1 but not p300. Standard and quantitative co-immunoprecipitation experiments readily detected a complex containing p53 and Notch-1 in MCF-7 cells. Formation of this complex was inhibited by dominant negative MAML1 (DN-MAML1) and stimulated by wild-type MAML1. Standard and quantitative far-Western experiments showed a complex including p53, Notch-1 and MAML1. Chromatin immunoprecipitation (ChIP) experiments showed that p53 can associate with Notch-dependent HEY1 promoter and this association is inhibited by DN-MAML1 and stimulated by wild-type MAML1. Our data support a model in which p53 associates with the Notch transcriptional complex (NTC) in a MAML1-dependent fashion, most likely through a p53-MAML1 interaction. In our cellular models, the effect of this association is to inhibit Notch-dependent transcription. Our data suggest that p53-null breast cancers may lack this Notch-modulatory mechanism, and that therapeutic strategies that activate wild-type p53 can indirectly cause inhibition of Notch transcriptional activity. This article is protected by copyright. All rights reserved.
Journal Title: Journal of cellular physiology
Volume: 230
Issue: 12
ISSN: 1097-4652; 0021-9541
Publisher: Unknown  
Date Published: 2015
Start Page: 3115
End Page: 3117
Language: ENG
DOI/URL:

10.1002/jcp.25052
Notes: LR: 20150604; CI: This article is protected by copyright. All rights reserved.; JID: 0050222; OTO: NOTNLM; 2015/01/02 [received]; 2015/04/26 [revised]; 2015/05/20 [accepted]; aheadofprint