title: Involvement of transcription repressor Snail in the regulation of human telomerase reverse transcriptase (hTERT) by transforming growth factor-β.
abstract: Human telomerase reverse transcriptase (hTERT), a catalytic subunit of telomerase, is the primary determinant for telomerase enzyme activity, which has been associated with cellular immortality. Expression of the hTERT gene is regulated by various extracellular (external) stimuli and is aberrantly up-regulated in more than 90% of cancers. Here we show that hTERT gene expression was repressed in response to transforming growth factor-β (TGF-β) by a mechanism dependent on transcription factors Snail and c-Myc. TGF-β activated Snail and down-regulated c-Myc gene expression. In addition, ectopic expression of Snail strongly inhibited hTERT promoter activity, although co-expression of c-Myc abrogated this effect. Chromatin immunoprecipitation (ChIP) analysis revealed that TGF-β decreased c-Myc occupancy and dramatically increased recruitment of Snail to the E-box motifs of the hTERT promoter, thereby repressing hTERT expression. Our findings suggest a dynamic alteration in hTERT promoter occupancy by Snail and c-Myc is the mechanistic basis for TGF-β-mediated regulation of hTERT.
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Republic of Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Yoo
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Republic of Korea.
authors.forename: Seoyoung
authors.initials: S
authors.lastname: Park
authors.affiliation: Research Institute for Basic Science, Sogang University, 35 Baekbeom-ro (Sinsu-dong), Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Jungsug
authors.initials: J
authors.lastname: Gwak
authors.affiliation: Research Institute for Basic Science, Sogang University, 35 Baekbeom-ro (Sinsu-dong), Mapo-gu, Seoul 121-742, Republic of Korea.
authors.forename: Bong Gun
authors.initials: BG
authors.lastname: Ju
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 136-702, Republic of Korea. Electronic address: ohsa@kookmin.ac.kr.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D002461:Cell Line, Transformed; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D008156:Luciferases; C509186:TERT protein, human; D019098:Telomerase
keywords: Human telomerase reverse transcriptase (hTERT); Snail; Transforming growth factor-β; c-Myc