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Repression of human telomerase reverse transcriptase using artificial zinc finger transcription factors

Authors
 Joon Hyung Sohn  ;  Byung-Il Yeh  ;  Jong-Whan Choi  ;  Joonho Yoon  ;  Jun Namkung  ;  Kwang-Kyun Park  ;  Hyun-Won Kim 
Citation
 MOLECULAR CANCER RESEARCH, Vol.8(2) : 246-253, 2010 
Journal Title
MOLECULAR CANCER RESEARCH
ISSN
 1541-7786 
Issue Date
2010
MeSH
Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/metabolism ; Binding Sites/genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics* ; Gene Targeting/methods ; Growth Inhibitors/chemical synthesis ; Growth Inhibitors/genetics ; Growth Inhibitors/metabolism ; Humans ; Promoter Regions, Genetic/drug effects ; Promoter Regions, Genetic/genetics ; RNA, Messenger/metabolism ; Regulatory Elements, Transcriptional/genetics ; Repressor Proteins/chemical synthesis ; Repressor Proteins/genetics* ; Repressor Proteins/metabolism ; Telomerase/genetics* ; Telomerase/metabolism ; Transcription Factors/chemical synthesis ; Transcription Factors/genetics* ; Transcription Factors/metabolism ; Transfection ; Zinc Fingers/genetics*
Abstract
Telomerase activation is a key step in the development of human cancers. Expression of the catalytic subunit, human telomerase reverse transcriptase (hTERT), represents the limiting factor for telomerase activity. In this study, we have used artificial zinc finger protein (ZFP) transcription factors (TF) to repress the expression of hTERT in human cancer cell lines at the transcriptional level. We have constructed four-fingered ZFPs derived from the human genome which binds 12-bp recognition sequences within the promoter of the hTERT gene and fused them with a KRAB repressor domain to create a potent transcriptional repressor. Luciferase activity was decreased by >80% in all of the transcriptional repressors with luciferase reporter assay. When they were transfected into the telomerase-positive HEK293 cell line, a decrease of mRNA level and telomerase activity together with shortening of telomere length was observed. Actual growth of HEK293 cells was also inhibited by transfection of artificial ZFP-TFs. The repression was maintained for 100 days of culture. The repression of telomerase expression by artificial ZFP-TFs targeting the promoter region of the hTERT presents a new promising strategy for inhibiting the growth of human cancer cells
Files in This Item:
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DOI
10.1158/1541-7786.MCR-09-0141
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Kwang Kyun(박광균)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/101594
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