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J Cell Physiol. 2015 Dec;230(12):3115-27. doi: 10.1002/jcp.25052.

p53 Modulates Notch Signaling in MCF-7 Breast Cancer Cells by Associating With the Notch Transcriptional Complex Via MAML1.

Author information

1
Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Chungbuk, Republic of Korea.
2
Cardinal Bernardin Cancer Center, Loyola University Chicago, Chicago, Illinois.
3
Department of Biochemistry, University of Mississippi, Jackson, Mississippi.
4
Cancer Institute, University of Mississippi, Jackson, Mississippi.
5
Stanley Scott Cancer Center, Louisiana State Health Sciences Center and Louisiana Cancer Research Consortium, New Orleans, Louisiana.
6
Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
7
Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
8
Eppley Cancer Center, University of Nebraska, Omaha, Nebraska.
9
College of Pharmacy, Gachon University, Incheon, Republic of Korea.
10
College of Pharmacy, Korea University, Sejong, Republic of Korea.
11
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
12
Department of Pharmacology, Georgetown University, Washington D.C.
13
Department of Pathology, University of Mississippi, Jackson, Mississippi.
14
Department of Neuroscience, University of Florida, Gainesville, Florida.
15
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, Massachusetts.

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.

PMID:
26033683
PMCID:
PMC4549197
DOI:
10.1002/jcp.25052
[Indexed for MEDLINE]
Free PMC Article

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