Abstract
Upregulation of human telomerase reverse transcriptase (hTERT) transcription accounts for the immortalization of greater than 85% of all human tumor cells. However, the mechanism whereby hTERT expression is activated remains unresolved. Specifically, recent data challenging the role of Myc/Max in E-box-dependent activation of hTERT expression suggests that other E-box-binding proteins regulate hTERT transcription. Indeed, we now demonstrate that two such proteins, upstream stimulatory factor (USF) 1 and 2, readily associate with two E-boxes in the hTERT promoter in vitro and in vivo primarily as heterodimers, whereas Myc/Max does not. The avid binding of USF1/2 heterodimers to these E-boxes occurs in both hTERT-positive and -negative cells. In contrast, USF1/2 activates the hTERT promoter exclusively in hTERT-positive cells in a manner that is enhanced by the coactivator p300 and attenuated upon inhibiting p38-MAP kinase, a known modulator of USF activity. Collectively, our data indicate that USF binding to the hTERT promoter may be transcriptionally neutral, or even repressive, in nonimmortalized hTERT-negative somatic cells, but stimulatory in hTERT-positive cells where USF1/2 contributes to the acquisition and maintenance of immortality.
MeSH terms
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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Binding Sites
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Cell Line, Transformed
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dimerization
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E-Box Elements
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic*
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Humans
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Imidazoles / pharmacology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphorylation
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Pyridines / pharmacology
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Telomerase / genetics*
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Telomerase / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Upstream Stimulatory Factors
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p38 Mitogen-Activated Protein Kinases
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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DNA-Binding Proteins
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Enzyme Inhibitors
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Imidazoles
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MAX protein, human
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Myc associated factor X
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Nuclear Proteins
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Proto-Oncogene Proteins c-myc
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Pyridines
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Trans-Activators
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Transcription Factors
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USF1 protein, human
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Upstream Stimulatory Factors
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Telomerase
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4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole