+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

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



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



Journal of Cellular Physiology 230(12): 3115-3127



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.

(PDF emailed within 0-6 h: $19.90)

Accession: 059289703

Download citation: RISBibTeXText

PMID: 26033683

DOI: 10.1002/jcp.25052


Related references

Notch modulates Wnt signalling by associating with Armadillo/b-catenin and regulating its transcriptional activity. Development (Cambridge, England) 132(8): 0, 2005

Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity. Development 132(8): 1819-1830, 2005

Stilbenoids remodel the DNA methylation patterns in breast cancer cells and inhibit oncogenic NOTCH signaling through epigenetic regulation of MAML2 transcriptional activity. Carcinogenesis 37(7): 656-668, 2017

Fringe modulates the notch signaling pathway by altering O-linked carbohydrate structures on notch. FASEB Journal 15(5): A864, March 8, 2001

Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling. Journal of Cell Biology 211(3): 605-617, 2016

MAML1 regulates EMT markers expression through NOTCH-independent pathway in breast cancer cell line MCF7. Biochemical and Biophysical Research Communications 2019, 2019

The Notch ligand delta-like 3 promotes tumor growth and inhibits Notch signaling in lung cancer cells in mice. Biochemical and Biophysical Research Communications 483(1): 488-494, 2016

The Notch signaling pathway: transcriptional regulation at Notch target genes. Cellular and Molecular Life Sciences 66(10): 1631-1646, 2009

Heterogeneity of breast cancer stem cells as evidenced with Notch-dependent and Notch-independent populations. Cancer Medicine 1(2): 105-113, 2013

MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nature Genetics 26(4): 484-489, 2000

PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells. Plos One 11(10): E0164660, 2016

A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1. Biochemical Journal 404(2): 289-298, 2007

Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer. Cancer Research 71(1): 277-286, 2011

Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways. Molecular Cancer 16(1): 57, 2017

O-fucose monosaccharide of Drosophila Notch has a temperature-sensitive function and cooperates with O-glucose glycan in Notch transport and Notch signaling activation. Journal of Biological Chemistry 290(1): 505-519, 2015