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ABCD2 Is a Direct Target of β-Catenin and TCF-4: Implications for X-Linked Adrenoleukodystrophy Therapy

Authors
 Chul-Yong Park  ;  Han-Soo Kim  ;  Jiho Jang  ;  Hyunji Lee  ;  Jae Souk Lee  ;  Jeong-Eun Yoo  ;  Dongjin R. Lee  ;  Dong-Wook Kim 
Citation
 PLoS One, Vol.8(2) : e56242, 2013 
Journal Title
 PLoS One 
ISSN
 1932-6203 
Issue Date
2013
Abstract
X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene that encodes the peroxisomal ATP-binding cassette (ABC) transporter subfamily D member 1 protein (ABCD1), which is referred to as the adrenoleukodystrophy protein (ALDP). Induction of the ABCD2 gene, the closest homolog of ABCD1, has been mentioned as a possible therapeutic option for the defective ABCD1 protein in X-ALD. However, little is known about the transcriptional regulation of ABCD2 gene expression. Here, through in silico analysis, we found two putative TCF-4 binding elements between nucleotide positions −360 and −260 of the promoter region of the ABCD2 gene. The transcriptional activity of the ABCD2 promoter was strongly increased by ectopic expression of β-catenin and TCF-4. In addition, mutation of either or both TCF-4 binding elements by site-directed mutagenesis decreased promoter activity. This was further validated by the finding that β-catenin and the promoter of the ABCD2 gene were pulled down with a β-catenin antibody in a chromatin immunoprecipitation assay. Moreover, real-time PCR analysis revealed that β-catenin and TCF-4 increased mRNA levels of ABCD2 in both a hepatocellular carcinoma cell line and primary fibroblasts from an X-ALD patient. Interestingly, we found that the levels of very long chain fatty acids were decreased by ectopic expression of ABCD2-GFP as well as β-catenin and TCF-4. Taken together, our results demonstrate for the first time the direct regulation of ABCD2 by β-catenin and TCF-4.
Files in This Item:
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DOI
10.1371/journal.pone.0056242
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Kim, Han Soo(김한수)
Park, Chul Yong(박철용) ORCID logo https://orcid.org/0000-0002-4467-9268
Yoo, Jeong Eun(유정은)
Lee, Dongjin R.(이동진)
Lee, Jae Souk(이재석)
Lee, Hyun Ji(이현지)
Jang, Ji Ho(장지호) ORCID logo https://orcid.org/0000-0001-5551-3514
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88164
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