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J. Biol. Chem., Vol. 277, Issue 41, 38230-38238, October 11, 2002
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From the Activation of telomerase is crucial for cells to
gain immortality. In human cells, telomerase activity is tightly
regulated by the expression of its catalytic subunit, human telomerase
reverse transcriptase (hTERT). In most normal human somatic cells,
hTERT is not expressed, and its suppression acts as an important
gatekeeper against tumorigenesis. Here we describe the systematic
analyses of hTERT promoter to understand the transcriptional repression mechanism of the hTERT gene in normal human somatic cells. Through the
serial deletion analysis of hTERT promoter in normal human fibroblasts,
we identified a critical repressive element on the hTERT promoter. The
repressive element formed DNA-protein complexes with Sp1 and Sp3 in
nuclear extracts. Using formaldehyde cross-linked chromatin
immunoprecipitation analysis, we found that Sp1 and Sp3
were associated with the endogenously repressed hTERT promoter in human
fibroblasts. Furthermore, Sp1 and Sp3 interacted with histone
deacetylase (HDAC) in these cells. Overexpression of dominant-negative mutants of Sp1 and Sp3, which contained mainly the HDAC2-binding domain, relieved the HDAC-mediated repression of the hTERT promoter. Taken together, these results suggest that Sp1 and Sp3 associate with
the hTERT promoter, recruiting HDAC for the localized deacetylation of
nucleosomal histones and transcriptional silencing of the hTERT gene in
normal human somatic cells.
Sp1 and Sp3 Recruit Histone Deacetylase to Repress Transcription
of Human Telomerase Reverse Transcriptase (hTERT) Promoter in Normal
Human Somatic Cells*
§,¶, and
**
National Creative Research Initiative Center
for Genetic Reprogramming, Institute for Molecular Biology and
Genetics, Seoul National University, Seoul 151-742, Korea, the
§ Department of Biological Sciences, Korea Advanced
Institute of Science and Technology, Taejon 305-701, Korea, and the
Institute of Chemistry and Cell Biology, Department of
Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, Boston, Massachusetts 02115
*
This work was supported by the Brain Korea 21 Project of the
Korean Ministry of Education, Molecular Medicine Research Group Program
M1-0106-00-01117, and the Creative Research Initiatives of the Korean
Ministry of Science and Technology.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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