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9-cis retinoic acid induces insulin-like growth factor binding protein-3 through DR-8 retinoic acid responsive elements

 Yoon Soo Chang  ;  Jae Yong Cho  ;  Hyun A. Cho  ;  Hyung Jung Kim  ;  Joon Chang  ;  Chul Min Ahn  ;  Sung Kyu Kim  ;  Se Kyu Kim 
 CANCER BIOLOGY & THERAPY, Vol.5(6) : 586-592, 2006 
Journal Title
Issue Date
Alitretinoin ; Cell Line, Tumor ; Cloning, Molecular ; Connective Tissue Growth Factor ; DNA Primers ; Gene Expression Regulation, Neoplastic ; Humans ; Immediate-Early Proteins/genetics* ; Insulin-Like Growth Factor Binding Protein 3/genetics* ; Insulin-Like Growth Factor Binding Protein 4/genetics* ; Insulin-Like Growth Factor Binding Protein 5/genetics* ; Insulin-Like Growth Factor Binding Protein 6/genetics* ; Insulin-Like Growth Factor Binding Proteins/genetics* ; Intercellular Signaling Peptides and Proteins/genetics* ; Plasmids ; Reverse Transcriptase Polymerase Chain Reaction ; Tretinoin/physiology*
insulin-like growth factor ; insulin-like growth factor binding protein-3 ; 9-cis retinoic acids ; retinoic acid receptor-β ; non-small cell lung cancer
Retinoic acids, which have shown potential chemopreventive and therapeutic activities for several neoplastic diseases in vitro, modulate the growth-promoting and anti-apoptotic activities of insulin-like growth factors (IGFs), in part by influencing the expression of insulin-like growth factor binding protein-3 (IGFBP-3). This study sought to investigate the effect of 9-cis retinoic acid (9cRA) on the expression of IGFBP-3 and the underlying mechanisms involving retinoic acid receptor-beta (RAR-beta). The pharmacologic activity of 9cRA was characterized by monitoring target modulation as well as by evaluating the underlying mechanisms in NSCLC cells. Treatment of 9cRA inhibited proliferation of a part of NSCLC cell lines including H460 cells in clinically-achievable concentrations and induced IGFBP-3 expression in dose- and time-dependent manners. Transient transfection with a reporter constructs driven by the human IGFBP-3 gene promoter indicated that 9cRA induces gene expression via the -534 to -445 region (relative to translation start site) of the IGFBP-3 promoter. Unilateral deletion and site-directed mutagenesis identified a retinoic acid responsive element (RARE), a direct repeat of two GGGTCA-related hexanucleotides separated by just 8 bp (DR-8-type response element). A cotransfection assay with a RAR-beta expression vector potentiated (and with siRNA for RAR-beta, diminished) the effect of 9cRA on IGFBP-3 expression. IGFBP-3 gene expression by 9cRA is mediated by a distinct DR-8 RARE located in the proximal region of the IGFBP promoter and involves the RAR-beta, a putative tumor suppressor in NSCLC.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Sung Kyu(김성규)
Kim, Se Kyu(김세규)
Kim, Hyung Jung(김형중) ORCID logo https://orcid.org/0000-0003-2498-0683
Ahn, Chul Min(안철민)
Chang, Yoon Soo(장윤수) ORCID logo https://orcid.org/0000-0003-3340-4223
Chang, Joon(장준) ORCID logo https://orcid.org/0000-0003-4542-6841
Cho, Jae Yong(조재용) ORCID logo https://orcid.org/0000-0002-0926-1819
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