PMID:24033289

Citation	Hiroi, R and Handa, RJ (2013) Estrogen receptor-β regulates human tryptophan hydroxylase-2 through an estrogen response element in the 5' untranslated region. J. Neurochem. 127:487-95
Abstract	In the dorsal raphe nucleus, 17β-estradiol (E2) increases the expression of the brain-specific, rate-limiting enzyme for serotonin biosynthesis, tryptophan hydroxylase-2 (Tph2). Although estrogen receptor beta (ERβ) has been localized to Tph2 neurons, little is known about the transcriptional regulation of the Tph2 gene by estrogen. Since the ERβ agonist, diarylpropionitrile (DPN) also increases Tph2 expression, we tested the hypothesis that E2 regulates the Tph2 promoter through direct interactions with ERβ. A serotonergic cell line, B14, which endogenously expresses ERβ was transiently transfected with a fragment of the human TPH2 5'-untranslated region (5'-UTR) cloned into a luciferase reporter vector (TPH2-luc). Treatment with E2 or DPN caused a dose-dependent increase of TPH2-luc activity. In contrast, E2 conjugated to bovine serum albumin, which is cell membrane impermeable, had no effect on TPH2-luc activity. An estrogen receptor (ER) antagonist blocked E2 or DPN-induced TPH2-luc activity suggesting a classical ER mechanism. In silico analysis revealed an estrogen-response element (ERE) half-site located within the TPH2 5'-UTR. Deletion and site-directed mutation of this site abolished ligand-induced TPH2-luc activity. These results support the concept that there is a direct and functional interaction between E2:ERβ and the ERE half-site of the TPH2 promoter to regulate Tph2 expression. We illustrate a direct regulation of the TPH2 transcription by estradiol and ERβ via a newly identified ERE half-site within the TPH2 promoter: (i) Estradiol- or an ERβ agonist-induced TPH2 transcription was blocked by an ER antagonist, while (ii) membrane impermeable form of estradiol did not induce transcription. (iii) Deletion or mutation of the ERE half-site abolished ligand-induced TPH2 transcription.
Links	PubMed PMC5825233 Online version:10.1111/jnc.12401
Keywords	5' Untranslated Regions; Animals; Cell Line; Estradiol/metabolism; Estradiol/pharmacology; Estrogen Receptor beta/agonists; Estrogen Receptor beta/metabolism; Estrogens/metabolism; Estrogens/pharmacology; Humans; Mice; Molecular Sequence Data; Nitriles/pharmacology; Promoter Regions, Genetic; Propionates/pharmacology; Rats; Response Elements; Signal Transduction; Transcription, Genetic; Tryptophan Hydroxylase/genetics; Tryptophan Hydroxylase/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ESR2	enables	GO:0030284: estrogen receptor activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:ESR2	involved_in	GO:0030520: intracellular estrogen receptor signaling pathway	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ESR2	enables	GO:0034056: estrogen response element binding	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
HUMAN:ESR2	involved_in	GO:0045944: positive regulation of transcription by RNA polymerase II	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:ESR2	involved_in	GO:0071392: cellular response to estradiol stimulus	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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