Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells
Abstract
The p53 tumor suppressor protein inhibits the formation of tumors through induction of cell cycle arrest and/or apoptosis. In the present study we demonstrated that p53 is also a powerful inhibitor of human telomerase reverse transcriptase (hTERT), a key component for telomerase. Activation of either exogenous temperature-sensitive (ts) p53 in BL41 Burkitt lymphoma cells or endogenous wild type (wt) p53 at a physiological level in MCF-7 breast carcinoma cells triggered a rapid downregulation of hTERT mRNA expression, independently of the induction of the p53 target gene p21. Co-transfection of an hTERT promoter construct with wt p53 but not mutant p53 in HeLa cells inhibited the hTERT promoter activity. Furthermore, the activation of the hTERT promoter in Drosophila Schneider SL2 cells was completely dependent on the ectopic expression of Sp1 and was abrogated by wt p53. Finally, wt p53 inhibited Sp1 binding to the hTERT proximal promoter by forming a p53-Sp1 complex. Since activation of telomerase, widely observed in human tumor cell lines and primary tumors, is a critical step in tumorigenesis, wt p53-triggered inhibition of hTERT/telomerase expression may reflect yet another mechanism of p53-mediated tumor suppression. Our findings provide new insights into both the biological function of p53 and the regulation of hTERT/telomerase expression.
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p53 represses hTERT transcription in an Sp1-dependent manner by forming a complex with Sp1.
“p53 was also shown to repress hTERT transcription in a Sp1-dependent manner.(71,72) It was proved that p53 can form a complex with Sp1, which disturbs the transcriptional activity of Sp1 and leads to transcriptional repression.(72)”
From Understanding and exploiting <i>hTERT</i> promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [72]
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Self-citation
- Authors
- Xu, D., Wang, Q., Gruber, A., Björkholm, M., Chen, Z., Zaid, A., Selivanova, G., Peterson, C., Wiman, K. G., & Pisa, P.
- Affiliations
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Stockholm University (SE)
- Linköping University (SE)
- Venue
- Oncogene
- Published
- 2000-10-26
- Volume
- 19
- Issue
- 45
- Pages
- 5123-5133
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2006565381
- Cited by
- 257
- References
- 41
- Citations by year
- 2026: 1 · 2025: 3 · 2023: 1 · 2022: 6 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 4 · 2017: 4 · 2016: 10 · 2015: 6 · 2014: 6 · 2013: 9 · 2012: 9
- FWCI
- 14.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- 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 › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- p53, telomerase reverse transcriptase, hTERT, telomerase activation, tumor suppression, Sp1, temperature-sensitive p53, Burkitt lymphoma cells, breast cancer cells
- MeSH terms
- Breast Neoplasms, Burkitt Lymphoma, DNA-Binding Proteins, Female, HeLa Cells, Humans, Mutation, Promoter Regions, Genetic, Protein Binding, RNA, RNA, Messenger, Transcription, Genetic, Tumor Cells, Cultured, Transcriptional Activation, Down-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cyclins, Sp1 Transcription Factor, Telomerase, RNA Stability, Cyclin-Dependent Kinase Inhibitor p21
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