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Targeting of therapeutic gene expression to the liver by using liver-type pyruvate kinase proximal promoter and the SV40 viral enhancer active in multiple cell types

Authors
 Cheol Won Park  ;  Young Mi Park  ;  Hyun Chul Lee  ;  Yong-ho Ahn  ;  Kyung-Sup Kim  ;  Bong Soo Cha  ;  Chul Woo Ahn  ;  Ji-Young Cha  ;  Seonock Woo  ;  Yongho Lee  ;  Geun Taek Lee 
Citation
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol.314(1) : 131-137, 2004 
Journal Title
 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 
ISSN
 0006-291X 
Issue Date
2004
MeSH
Cell Line, Tumor ; Cells, Cultured ; DNA-Binding Proteins/genetics* ; DNA-Binding Proteins/metabolism* ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation/genetics ; Gene Targeting/methods* ; Genetic Therapy/methods ; Hepatoblastoma/genetics ; Hepatoblastoma/metabolism ; Hepatocyte Nuclear Factor 1 ; Hepatocyte Nuclear Factor 1-alpha ; Hepatocyte Nuclear Factor 1-beta ; Humans ; Kidney/metabolism ; Liver/metabolism* ; Nuclear Proteins* ; Organ Specificity ; Promoter Regions, Genetic/genetics ; Pyruvate Kinase/genetics* ; Pyruvate Kinase/metabolism* ; Transcription Factors/genetics* ; Transcription Factors/metabolism*
Keywords
Gene therapy ; L-PK proximal promoter ; HNF-1α ; SV40 viral enhancer ; Tissue-specific gene expression
Abstract
To achieve the liver-directed expression in sufficient amounts of therapeutic genes for successful and safe gene therapy, natural liver-specific promoters can be used to direct the expression of therapeutic genes in the liver, whereas strong viral enhancers were used to obtain sufficient amounts of expressed therapeutic gene products. However, very often use of either the former or the latter does not guarantee both potent and liver-specific therapeutic gene expression. Here we conglomerate them and thus create a potent tissue-specific promoter by characterizing and using the liver-type pyruvate kinase proximal promoter (LPKPP) harboring its TATA box and a HNF-1α binding site. Alone it hardly activated its reporter gene expression in non-hepatocytes or hepatocytes. However, in the presence of the SV40 viral enhancer (SV40VE), which is active in multiple cell types, it was able to potently activate its reporter gene expression specifically in hepatocytes. The tissue-specific activation of the LPKPP by the viral enhancer was attributed to HNF-1α binding to the LPKPP. Taken together, these results support the idea that the constitutively active SV40VE could be used to activate the LPKPP in a tissue-specific manner in the presence of HNF-1α. To our knowledge, this is the first study to utilize HNF-1α and its binding site, in the context of the LPKPP, to generate a basal promoter that is transcriptionally activated potently in a tissue-specific manner by a viral enhancer that is active in multiple cell types.
Full Text
http://www.sciencedirect.com/science/article/pii/S0006291X03026585
DOI
10.1016/j.bbrc.2003.12.064
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sup(김경섭) ORCID logo https://orcid.org/0000-0001-8483-8537
Ahn, Yong Ho(안용호) ORCID logo https://orcid.org/0000-0002-4133-0757
Ahn, Chul Woo(안철우) ORCID logo https://orcid.org/0000-0003-3733-7486
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Hyun Chul(이현철)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/111546
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