p53-dependent Down-regulation of Telomerase Is Mediated by p21
Open accessAbstract
Inactivation of p53 and activation of telomerase occur in the majority of human cancers, raising the possibility of a link between these two pathways. Overexpression of wild-type p53 down-regulates the enzymatic activity of telomerase in various cancer cell lines through transcriptional repression of its catalytic subunit, human telomerase reverse transcriptase (hTERT). In this study, we re-evaluated the role of p53 in telomerase regulation using isogenic cell lines expressing physiological levels of p53. We demonstrate that endogenous wild-type p53 was able to down-regulate telomerase activity, hTERT mRNA levels, and promoter activity; however, the ability to repress hTERT expression was found to be cell type-specific. The integrity of the DNA-binding core domain, the N-terminal transactivation domain, and the C-terminal oligomerization domains of p53 was essential for hTERT promoter repression, whereas the proline-rich domain and the extreme C terminus were not required. Southwestern and chromatin immunoprecipitation experiments demonstrated lack of p53 binding to the hTERT promoter, raising the possibility of an indirect repressive mechanism. The down-regulation of hTERT promoter activity was abolished by a dominant-negative E2F1 mutant. Mutational analysis identified a specific E2F site responsible for p53-mediated repression. Knockdown of the key p53 transcriptional target, p21, was sufficient to eliminate the p53-dependent repression of hTERT. Inactivation of the Rb family using either viral oncoproteins or RNA interference attenuated the repression. Inhibition of histone deacetylases also interfered with the repression of hTERT by p53. Therefore, our results suggest that repression of hTERT by endogenous p53 is mediated by p21 and E2F.
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p130 and E2F4 are recruited to cell cycle gene promoters when p21 is activated by p53.
“Consistent with this notion, p130 and E2F4 are recruited to cell cycle gene promoters when p21 is activated by p53.98, 99”
From Census and evaluation of p53 target genes (2017) · cites this paper as [99]
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- Authors
- Shats, I., Milyavsky, M., Tang, X., Stambolsky, P., Erez, N., Brosh, R., Kogan, I., Braunstein, I., Tzukerman, M., Ginsberg, D., & Rotter, V.
- Affiliations
- Weizmann Institute of Science (IL)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Rotter, Varda
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 279
- Issue
- 49
- Pages
- 50976-50985
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2118388996
- Cited by
- 133
- References
- 66
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2021: 4 · 2020: 2 · 2019: 8 · 2018: 2 · 2017: 8 · 2016: 6 · 2015: 5 · 2014: 7 · 2013: 8 · 2012: 12
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- p53, telomerase, hTERT, p21, E2F1, transcriptional repression, hTERT promoter, histone deacetylase, cancer
- MeSH terms
- Base Sequence, DNA, DNA Mutational Analysis, DNA-Binding Proteins, Histone Deacetylases, Humans, Luciferases, Molecular Sequence Data, Mutation, Neoplasms, Plasmids, Proline, Promoter Regions, Genetic, Protein Binding, RNA, Messenger, Transcription Factors, Transcription, Genetic, Transfection, Blotting, Southern, Blotting, Western, Transcriptional Activation, Down-Regulation, Tumor Suppressor Protein p53, Retinoblastoma Protein, Point Mutation, Protein Structure, Tertiary, Genes, Reporter, Cell Cycle Proteins, Telomerase, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Line, Tumor, Chromatin Immunoprecipitation, E2F Transcription Factors, E2F1 Transcription Factor, Cyclin-Dependent Kinase Inhibitor p21
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