The promoters of human cell cycle genes integrate signals from two tumor suppressive pathways during cellular transformation
Open accessAbstract
Deciphering regulatory events that drive malignant transformation represents a major challenge for systems biology. Here, we analyzed genome-wide transcription profiling of an in vitro cancerous transformation process. We focused on a cluster of genes whose expression levels increased as a function of p53 and p16(INK4A) tumor suppressors inactivation. This cluster predominantly consists of cell cycle genes and constitutes a signature of a diversity of cancers. By linking expression profiles of the genes in the cluster with the dynamic behavior of p53 and p16(INK4A), we identified a promoter architecture that integrates signals from the two tumor suppressive channels and that maps their activity onto distinct levels of expression of the cell cycle genes, which, in turn, correspond to different cellular proliferation rates. Taking components of the mitotic spindle as an example, we experimentally verified our predictions that p53-mediated transcriptional repression of several of these novel targets is dependent on the activities of p21, NFY, and E2F. Our study demonstrates how a well-controlled transformation process allows linking between gene expression, promoter architecture, and activity of upstream signaling molecules.
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Numerous cell cycle genes are downregulated via the p53-p21 pathway.
“Following these reports, numerous cell cycle genes were found to be downregulated via the p53-p21 pathway.92, 93, 94, 95, 96, 97”
From Census and evaluation of p53 target genes (2017) · cites this paper as [93]
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- Authors
- Tabach, Y., Milyavsky, M., Shats, I., Brosh, R., Zuk, O., Yitzhaky, A., Mantovani, R., Domany, E., Rotter, V., & Pilpel, Y.
- Affiliations
- Weizmann Institute of Science (IL)
- University of Milan (IT)
- Corresponding author
- Rotter, Varda
- Pilpel, Yitzhak
- Venue
- Molecular Systems Biology
- Published
- 2005-10-18
- Volume
- 1
- Issue
- 1
- Pages
- 2005.0022-2005.0022
- ISSN
- 1744-4292 (ISSN-L)
- PMC
- PMC1681464
- OpenAlex
- W2146032366
- Cited by
- 72
- References
- 90
- Citations by year
- 2024: 1 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 5
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Systems Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- arXiv (Cornell University) (submittedVersion)
- arXiv (Cornell University)
- Funders
- Flight Attendant Medical Research Institute
- Minerva Foundation
- National Institutes of Health
- National Cancer Institute (5 POI CA 65930-06, P01CA065930)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- cell cycle genes, promoter architecture, p53, p16INK4a, tumor suppressor inactivation, cell transformation, transcriptional repression, mitotic spindle, p21, NF-Y, E2F transcription factors, gene expression profiling, cancer signatures, proliferation rate
- MeSH terms
- Animals, Cell Division, Cell Line, Transformed, Cell Transformation, Neoplastic, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Humans, Mice, Nude, Spindle Apparatus, Promoter Regions, Genetic, Recombinant Fusion Proteins, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Transplantation, Heterologous, Genes, Tumor Suppressor, Genes, p53, Tumor Suppressor Protein p53, Cell Cycle Proteins, Genes, cdc, Telomerase, Computational Biology, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, Gene Expression Profiling, Mice
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