BACKGROUND: Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in brain serotonin (5-HT) biosynthesis. Although dysfunction of 5-HT neurotransmission has been implicated in a variety of neuropsychiatric conditions, the human TPH2 promoter has not been characterized in vitro.
METHODS: The functional relevance of TPH2 promoter polymorphisms was determined with luciferase assays in primary serotonergic neurons from rat raphe nuclei and in human small cell lung carcinoma cells (SHP-77 cells). We also investigated transcription factor binding to the variant promoter sequence with electrophoretic mobility shift assay (EMSA).
RESULTS: The polymorphism rs11178997 of the human TPH2 promoter significantly reduced TPH2 transcriptional activity by 22% and 7% in primary serotonergic neurons and in SHP-77 cells, respectively. In contrast, no significant differences in promoter activity were observed for the G- and T-alleles of rs4570625. The EMSA revealed reduced binding of the transcription factor POU3F2 (also known as Brn-2, N-Oct-3) to the A-allele of the polymorphism rs11178997. Overexpression of POU3F2 resulted in a robust activation of the TPH2 promoter (2.7-fold).
CONCLUSIONS: Our data suggest that the human TPH2 promoter polymorphism rs11178997 impacts on gene expression, which might have implications for the development and function of the serotonergic system in the brain.
|Number of pages||7|
|Publication status||Published - 1 Dec 2007|
- Blotting, Northern
- Blotting, Western
- Carcinoma, Small Cell
- Cell Line, Tumor
- DNA, Neoplasm
- Electrophoretic Mobility Shift Assay
- Genetic Vectors
- Polymorphism, Genetic
- Promoter Regions, Genetic
- RNA, Messenger
- Raphe Nuclei
- Tryptophan Hydroxylase
- Journal Article
- Research Support, Non-U.S. Gov't