Function of AP-1 in Transcription of the Telomerase Reverse Transcriptase Gene (TERT) in Human and Mouse Cells
Open accessAbstract
The transcriptional regulation of the human telomerase catalytic subunit (hTERT) plays a critical role in telomerase activity. Approximately 200 bp of the proximal core promoter is responsible for basic hTERT expression; however, the function of the distal regulatory elements remains unclear. The transcription factor activator protein 1 (AP-1) is involved in cellular proliferation, differentiation, carcinogenesis, and apoptosis and is expressed broadly in both cancer and normal cells. There are several putative AP-1 sites in the hTERT promoter, but their functions are unknown. The present study examined the regulatory role of AP-1 in hTERT gene transcription. Overexpression of AP-1 leads to transcriptional suppression of hTERT in cancer cells. The combination of c-Fos and c-Jun or c-Fos and JunD strongly suppresses hTERT promoter activity in transient-expression analyses. The hTERT promoter region between -2000 and -378 is responsible for this function. Gel shift and supershift analyses, as well as ChIP, show binding of JunD and c-Jun on two putative AP-1 sites within this region. Mutations in the AP-1 binding sites rescued suppressions caused by AP-1, suggesting this is a direct regulation of the hTERT promoter. In contrast, there was no effect on mTERT expression or mTERT promoter activity by AP-1 overexpression in mouse fibroblasts. The species-specific function of AP-1 in TERT expression may in part help explain the difference in telomerase activity between normal human and mouse cells.
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AP-1 has no effect on the mouse TERT promoter despite similar binding sites.
“Of particular interest is the observation that AP-1 had no effect on the mouse TERT (mTERT ) promoter although it has similar binding sites for AP-1.”
From Understanding and exploiting <i>hTERT</i> promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [28]
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- Authors
- Takakura, M., Kyo, S., Inoue, M., Wright, W. E., & Shay, J. W.
- Affiliations
- Kanazawa University (JP)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Shay, Jerry W.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-09-01
- Volume
- 25
- Issue
- 18
- Pages
- 8037-8043
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1234330
- OpenAlex
- W2114840351
- Cited by
- 107
- References
- 47
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 2 · 2021: 5 · 2020: 1 · 2019: 4 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 6 · 2014: 7 · 2013: 7 · 2012: 7
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG07992, R01AG007992)
- National Cancer Institute (CA 70907, R01CA085363, P50CA070907, CA 85363)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- activator protein-1, telomerase reverse transcriptase, c-fos, c-Jun, JunD, AP-1 binding site, telomerase regulation, species-specific gene regulation, cancer cells, transcriptional repression
- MeSH terms
- Animals, Base Sequence, Binding Sites, DNA-Binding Proteins, HeLa Cells, Humans, Molecular Sequence Data, Mutation, Promoter Regions, Genetic, Transcription, Genetic, Transcriptional Activation, Gene Expression Regulation, Enzymologic, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-fos, Transcription Factor AP-1, Telomerase, NIH 3T3 Cells, Mice
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