Regulation of the tyrosine hydroxylase gene promoter by histone deacetylase inhibitors.
Tyrosine hydroxylase (TH) catalyzes the conversion of L-tyrosine to 3,4-dihydroxy-L-phenylalanine, which is the first and rate-limiting step in catecholamine biosynthesis. In the present study, we report that treatment with the histone deacetylase (HDAC) inhibitors, trichostatin A (TSA) or sodium butyrate, prominently induces the TH promoter activity in both non-neuronal and neuronal cell lines. By analyzing a series of deletional reporter constructs, we also determined that the proximal 151bp region of the TH promoter is largely responsible for TSA-mediated activation. Finally, we found that mutation of the Sp1 or CRE site, residing in the proximal area, abolishes TSA-mediated activation, strongly suggesting that the Sp1 and CRE sites may mediate TH promoter activation by inhibition of HDAC. In summary, our results provide a novel regulatory frame in which modulation of chromatin structure by histone deacetylase may contribute to transcriptional regulation of the TH via the Sp1 and/or CRE site.
Kim
Hee-Sun
HS
Department of Neuroscience, Ewha Institute of Neuroscience, College of Medicine, Ewha Womans University, Seoul, Republic of Korea. hskimp@mm.ewha.ac.kr
Park
Jin-Sun
JS
Hong
Seok-Jong
SJ
Woo
Moon-Sook
MS
Kim
So-Young
SY
Kim
Kwang-Soo
KS
D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005910:Glioma / Q000201:enzymology / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism*
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009097:Multienzyme Complexes; C012589:trichostatin A; D014446:Tyrosine 3-Monooxygenase; D006655:Histone Deacetylases