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Published on: August 12, 2015
Identification of a p53-repressed gene module in breast cancer cells
Takafumi Miyamoto1, Chizu Tanikawa1, Varalee Yodsurang2
1Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Abstract:
The p53 protein is a sophisticated transcription factor that regulates dozens of target genes simultaneously in accordance with the cellular circumstances. Although considerable efforts have been made to elucidate the functions of p53-induced genes, a holistic understanding of the orchestrated signaling network repressed by p53 remains elusive. Here, we performed a systematic analysis to identify simultaneously regulated p53-repressed genes in breast cancer cells. Consequently, 28 genes were designated as the p53-repressed gene module, whose gene components were simultaneously suppressed in breast cancer cells treated with Adriamycin. A ChIP-seq database showed that p53 does not preferably bind to the region around the transcription start site of the p53-repressed gene module elements compared with that of p53-induced genes. Furthermore, we demonstrated that p21/CDKN1A plays a pivotal role in the suppression of the p53-repressed gene module in breast cancer cells. Finally, we showed that appropriate suppression of some genes belonging to the p53-repressed gene module contributed to a better prognosis of breast cancer patients. Taken together, these findings disentangle the gene regulatory network underlying the built-in p53-mediated tumor suppression system.
Insights
This study identifies a module of 28 genes repressed by the p53 protein in breast cancer cells, revealing a new aspect of p53
Area of Science:
- Molecular Biology
- Cancer Genomics
- Cellular Signaling
Background:
- The p53 protein is a critical transcription factor regulating cellular responses.
- Understanding p53-repressed genes is crucial for a complete picture of its tumor suppressor functions.
- Existing research primarily focuses on p53-induced genes, leaving p53-repressed networks underexplored.
Purpose of the Study:
- To systematically identify genes simultaneously repressed by p53 in breast cancer cells.
- To investigate the regulatory mechanisms and clinical significance of p53-repressed genes.
- To elucidate the role of p53-repressed gene modules in the p53-mediated tumor suppression system.
Main Methods:
- Systematic analysis of gene expression in breast cancer cells treated with Adriamycin.
- Utilized ChIP-seq database to examine p53 binding patterns.
- Investigated the role of p21/CDKN1A in regulating p53-repressed genes.
Main Results:
- Identified a module of 28 simultaneously regulated p53-repressed genes.
- Found that p53 binding is not preferentially located near the transcription start sites of these repressed genes.
- Demonstrated p21/CDKN1A's crucial role in suppressing the identified p53-repressed gene module.
- Showed that suppression of some genes in this module correlates with better breast cancer patient prognosis.
Conclusions:
- Disentangled a novel gene regulatory network controlled by p53 repression.
- Highlighted the importance of p53-repressed genes in the p53 tumor suppression pathway.
- Suggested that targeting p53-repressed genes could offer new therapeutic strategies for breast cancer.
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