title: ABCD2 is a direct target of β-catenin and TCF-4: implications for X-linked adrenoleukodystrophy therapy.
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.
authors: Department of Physiology, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea.
authors: Chul-Yong
authors: CY
authors: Park
authors: Han-Soo
authors: HS
authors: Kim
authors: Jiho
authors: J
authors: Jang
authors: Hyunji
authors: H
authors: Lee
authors: Jae Souk
authors: JS
authors: Lee
authors: Jeong-Eun
authors: JE
authors: Yoo
authors: Dongjin R
authors: DR
authors: Lee
authors: Dong-Wook
authors: DW
authors: Kim
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000326:Adrenoleukodystrophy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C431694:ABCD2 protein, human; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D049452:Green Fluorescent Proteins