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Identification and characterization of negative regulatory elements of the human telomerase catalytic subunit (hTERT) gene promoter: possible role of MZF-2 in transcriptional repression of hTERT
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Human telomerase reverse transcriptase (hTERT) is a catalytic subunit of human telomerase and is a critical determinant of the enzymatic activity of telomerase. Expression of hTERT is known to be regulated mainly at the transcriptional level. In the present study, using transient expression assays, we identified a 400 bp silencer of the hTERT promoter between -776 and -378 upstream of the proximal core promoter. The inhibitory effects of this silencer were enhanced with cellular differentiation. A computer-assisted homology search identified multiple binding motifs for myeloid-specific zinc finger protein 2 (MZF-2) within this region. Mutation introduced in these sites resulted in significant activation of hTERT transcription. Gel shift assays demonstrated that MZF-2 proteins specifically bound to these sites. Overexpression of MZF-2 in cells led to down-regulation of hTERT transcription as well as telomerase activity. These findings suggest that the 400 bp region upstream of the hTERT core promoter that we identified functions as a negative regulatory region and that MZF-2 may be an effector of negative regulation of hTERT.
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“Several transcriptional repressors, including Wilms' tumor 1 tumor suppressor (WT1) and myeloidspecific zinc finger protein-2 (MZF-2) are also known to repress hTERT transcription via binding to their specific sites on the promoter, although the mechanisms of repression remain unclear.(73,74)”
From Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [74]
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Metadata
- Authors
- Fujimoto, K., Kyo, S., Takakura, M., Kanaya, T., Kitagawa, Y., Itoh, H., Takahashi, M., & Inoue, M.
- Affiliations
- Kanazawa University (JP)
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-07-01
- Volume
- 28
- Issue
- 13
- Pages
- 2557-2562
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC102701
- OpenAlex
- W2146670318
- Cited by
- 116
- References
- 33
- Citations by year
- 2024: 2 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 5 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 1
- FWCI
- 5.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nucleic Acids Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- hTERT, human telomerase reverse transcriptase, telomerase, negative regulatory element, transcriptional repression, zinc finger transcription factor, cell differentiation, telomerase activity, transcriptional regulation
- MeSH terms
- Base Sequence, Binding Sites, Cell Differentiation, DNA, DNA-Binding Proteins, Humans, Mutation, Promoter Regions, Genetic, Repressor Proteins, RNA, RNA, Messenger, Transcription Factors, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Down-Regulation, Zinc Fingers, Consensus Sequence, Telomerase, Reverse Transcriptase Polymerase Chain Reaction, Catalytic Domain, Response Elements, Gene Silencing, Kruppel-Like Transcription Factors
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