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ETS variant transcription factor 5 and c-Myc cooperate in derepressing the human telomerase gene promoter via composite ETS/E-box motifs
- Source :
- J Biol Chem
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- The human telomerase gene (hTERT) is repressed in most somatic cells. How transcription factors activate the hTERT promoter in its repressive chromatin environment is unknown. Here, we report that the ETS family protein ETS variant transcription factor 5 (ETV5) mediates epidermal growth factor (EGF)-induced hTERT expression in MCF10A cells. This activation required MYC proto-oncogene bHLH transcription factor (c-Myc) and depended on the chromatin state of the hTERT promoter. Using chromatinized bacterial artificial chromosome (BAC) reporters in human fibroblasts, we found that ETV5 and c-Myc/MYC-associated factor X (MAX) synergistically activate the hTERT promoter via two identical, but inverted, composite Ets/E-box motifs enclosing the core promoter. Mutations of Ets or E-box sites in either DNA motif abolished the activation and reduced or eliminated the synergism. ETV5 and c-Myc facilitated each other's binding to the hTERT promoter. ETV5 bound to the hTERT promoter in both telomerase-negative and -positive cells, but it activated the repressed hTERT promoter and altered histone modifications only in telomerase-negative cells. The synergistic ETV5/c-Myc activation disappeared when hTERT promoter repression became relieved because of the loss of distal regulatory elements in chimeric human/mouse BAC reporters. Our results suggest that the binding of c-Myc and ETS family proteins to the Ets/E-box motifs derepresses the hTERT promoter by inducing an active promoter configuration, providing a mechanistic insight into hTERT activation during tumorigenesis.
- Subjects :
- 0301 basic medicine
cells
E-box
Response Elements
Proto-Oncogene Mas
Biochemistry
Gene Expression Regulation, Enzymologic
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Transcription (biology)
Cell Line, Tumor
Transcriptional regulation
Humans
Gene Regulation
Telomerase reverse transcriptase
Telomerase
neoplasms
Molecular Biology
Transcription factor
Cells, Cultured
030102 biochemistry & molecular biology
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Chemistry
ETS transcription factor family
Promoter
Cell Biology
Chromatin
Cell biology
DNA-Binding Proteins
enzymes and coenzymes (carbohydrates)
030104 developmental biology
embryonic structures
biological phenomena, cell phenomena, and immunity
Transcription Factors
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 295
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....4aa6c3e835f2e3b5503424f2fd6acf5d