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- W2005751522 abstract "Aim: Since previous functional studies of short haplotypes and polymorphic sites of SLC6A3 have shown variant-dependent and drug-sensitive promoter activity, this study aimed to understand whether a large SLC6A3 regulatory region, containing these small haplotypes and polymorphic sites, can display haplotype-dependent promoter activity in a drug-sensitive and pathway-related manner. Materials & methods: By creating and using a single copy number luciferase-reporter vector, we examined regulation of two different SLC6A3 haplotypes (A and B) of the 5´ 18-kb promoter and two known downstream regulatory variable number tandem repeats by 17 drugs in four different cellular models. Results: The two regulatory haplotypes displayed up to 3.2-fold difference in promoter activity. The regulations were drug selective (37.5% of the drugs showed effects), and both haplotype and cell type dependent. Pathway analysis revealed at least 13 main signaling hubs targeting SLC6A3, including histone deacetylation, AKT, PKC and CK2 α-chains. Conclusion:SLC6A3 may be regulated via either its promoter or the variable number tandem repeats independently by specific signaling pathways and in a haplotype-dependent manner. Furthermore, we have developed the first pathway map for SLC6A3 regulation. These findings provide a framework for understanding complex and variant-dependent regulations of SLC6A3. Original submitted 12 June 2013; Revision submitted 17 July 2013" @default.
- W2005751522 created "2016-06-24" @default.
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- W2005751522 date "2013-09-01" @default.
- W2005751522 modified "2023-09-27" @default.
- W2005751522 title "Human dopamine transporter gene: differential regulation of 18-kb haplotypes" @default.
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- W2005751522 doi "https://doi.org/10.2217/pgs.13.141" @default.
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