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

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,...

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Bibliographic Details
Published in:Nucleic acids research 2000-07, Vol.28 (13), p.2557-2562
Main Authors: Fujimoto, K, Kyo, S, Takakura, M, Kanaya, T, Kitagawa, Y, Itoh, H, Takahashi, M, Inoue, M
Format: Article
Language:English
Subjects:
Base Sequence
Binding Sites
Catalytic Domain - genetics
Cell Differentiation
Consensus Sequence - genetics
DNA - genetics
DNA - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Down-Regulation
Gene Silencing
hTERT gene
Humans
Kruppel-Like Transcription Factors
Mutation - genetics
MZF-2 protein
Promoter Regions, Genetic - genetics
Repressor Proteins - genetics
Repressor Proteins - metabolism
Response Elements - genetics
Reverse Transcriptase Polymerase Chain Reaction
RNA
RNA, Messenger - genetics
RNA, Messenger - metabolism
telomerase
Telomerase - genetics
Telomerase - metabolism
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic - genetics
Transfection
Tumor Cells, Cultured
Zinc Fingers
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/28.13.2557