title: Transcriptional regulation of ATP2C1 gene by Sp1 and YY1 and reduced function of its promoter in Hailey-Hailey disease keratinocytes.
abstract: Hailey-Hailey disease (HHD) is a blistering skin disease caused by malfunction of the Ca2+-dependent ATPase, ATP2C1. In this study, key regulatory regions necessary for the expression of the gene encoding human ATP2C1 were investigated. The transient reporter assay demonstrated that region +21/+57 was necessary for activation of the ATP2C1 promoter, and the electrophoretic mobility shift assay demonstrated that the region was recognized by the transcription factors, Sp1 and YY1. In accordance with this result, when Sp1 or YY1 was overexpressed in keratinocytes, an obvious increase in ATP2C1 promoter activity was observed, which was in contrast with the case where a mutant promoter lacking the binding sites for Sp1 and YY1 was used as the reporter. Ca2+-stimulation signal increased nuclear Sp1 proteins and ATP2C1 mRNA levels in normal keratinocytes. In contrast, both these increases were suppressed in keratinocytes from HHD patients. These results indicate that Sp1 and YY1 transactivate the human ATP2C1 promoter via cis-enhancing elements and that incomplete upregulation of ATP2C1 transcription contributes to the keratinocyte-specific pathogenesis of HHD. This is a report describing the regulation of the expression of ATP2C1.
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawada
authors.forename: Chiharu
authors.initials: C
authors.lastname: Nishiyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takagi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tokura
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakano
authors.forename: Keiko
authors.initials: K
authors.lastname: Maeda
authors.forename: Nobuyasu
authors.initials: N
authors.lastname: Mayuzumi
authors.forename: Shigaku
authors.initials: S
authors.lastname: Ikeda
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008969:Molecular Sequence Data; D016506:Pemphigus, Benign Familial / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D050986:YY1 Transcription Factor
chemical_list: D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium