Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotine is a powerful stimulant of the sympathoadrenal system, causing the release of peripheral catecholamines and activation of catecholamine biosynthesis. In previous reports, we have studied the mechanisms by which short-term nicotine treatment regulates tyrosine hydroxylase (TH) in adrenal medulla. In this report, we study the effects of chronic nicotine treatment on adrenal TH gene expression. Rats were injected with either saline or nicotine twice per day for up to 14 days. Chronic nicotine treatment elicited long-lasting, dose-dependent increases in the levels of adrenal TH mRNA, TH protein, and TH activity. In contrast, a single injection of nicotine elicited only a small increase in adrenal TH mRNA levels, which was transient and did not result in the induction of TH enzyme. Chronic nicotine administration also elicited a sustained increase in adrenal TH gene transcription rate, which persisted for up to 7 days after the final nicotine injection. This sustained transcriptional response correlated with a modest sustained increase in adrenal TH AP1 binding, but not in the levels of Fra-2 or other fos or jun proteins. These results demonstrate that repeated nicotine injections administered chronically over 1 to 2 weeks lead to sustained stimulation of the TH gene and consequent induction of TH gene expression in rat adrenal medulla. These studies support the hypothesis that chronic nicotine administration produces long-lasting cellular changes in adrenal medulla that lead to sustained transcriptional responses.
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PMID:Chronic nicotine treatment leads to sustained stimulation of tyrosine hydroxylase gene transcription rate in rat adrenal medulla. 1253 9

Several treatments which regulate tyrosine hydroxylase (TH) transcription, such as stress in vivo, or 12-O-tetradecanoylphorbol-13-acetate (TPA) in cell culture, induce both Egr1 and AP1 factors. Previously, we identified a functional Egr1 motif overlapping with Sp1 site in the rat TH promoter. Its response to Egr1 also required the presence of an AP1/Ebox motif. Here, we further examined the cross-talk between these sites. Insertion of 10- or 20-bp between the Sp1/Egr1 and AP1/Ebox elements, reduced the ability of Egr1 to upregulate luciferase reporter activity controlled by the proximal 272 nucleotides of the rat TH promoter in PC12 cells. Electrophoretic mobility shift assays with nuclear extracts from TPA treated cells were used to identify the composition of the factors which bound the AP1/Ebox motif and whether there is competition with factors which bind the Sp1/Egr1 motif. The complexes formed with labeled AP1/E box oligonucleotide were reduced or supershifted with antisera to Fos family, c-Fos, Fra-2, and Jun D. Excess Sp1/Egr1 oligonucleotide or anti Egr1 antisera did not compete. Fra-2 was a major component of the complex after 2-4 h TPA. Transfection of PC12 cells with Fra-2 induced reporter activity requiring the AP1, but not the Egr1 motif. However, when cotransfected with Fra-2, Egr1 expression plasmids elicited lower induction of luciferase activity than observed with Egr1 alone. Our results suggest that although it does not compete for binding to the promoter, Egr1 can modulate the regulation of TH transcription by AP1 factors.
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PMID:Interactions between Egr1 and AP1 factors in regulation of tyrosine hydroxylase transcription. 1267 Jul 3

Recently we have shown that in vitro binding of the proximal part of the human tyrosine hydroxylase gene to the nuclear matrix is correlated with its transcriptional activity. The strongest binding potential was predicted by computing for the first intron sequence (Lenartowski & Goc, 2002, Neurosci Lett.; 330: 151-154). In this study a 16 kb fragment of the bovine genomic DNA containing the tyrosine hydroxylase gene was investigated for its affinity to the nuclear matrix. Only a 950 bp fragment encoding the distal part of the first intron, second exon and a few nucleotides of the second intron bound to the nuclear matrix. The binding was independent of the tissue-specific tyrosine hydroxylase gene activation. The fragment was subcloned and sequenced. Computer search pointed to one potential intronic matrix attachment region with two AP1-like sites embedded in the sequence. We conclude that even if the position of the matrix binding region is conserved among the tyrosine hydroxylase genes in mammals, its tissue specificity and/or function is not preserved or is achieved by different mechanisms.
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PMID:The bovine tyrosine hydroxylase gene associates in vitro with the nuclear matrix by its first intron sequence. 1451 67

In neurons and neuroendocrine cells, tyrosine hydroxylase (TH) gene expression is induced by stimuli that elevate cAMP, by depolarization, and by hypoxia. Using these stimuli, we examined TH promoter mutants, cAMP response element binding protein (CREB) phosphorylation site mutants, and transcriptional interference with dominant negative transcription factors to assess the relative contributions of CREB/AP-1 family members to the regulation of basal and inducible TH transcription in PC12 cells. We found that basal transcription depends on transcription factor activity at the partial dyad (-17 bp), CRE (-45 bp), and AP1 (-205 bp) elements. Induced transcription is regulated primarily by activity at the CRE, with only small contributions from the AP1 or hypoxia response element 1 (HRE1; -225 bp) elements, regardless of inducing stimulus. CREB, ATF-1, and CREMtau all mediate CRE-dependent transcription, with CREB and CREMtau being more effective than ATF-1. Phosphorylation of CREB on Ser133, but not on Ser142 or Ser143, is required for induced transcription, regardless of inducing stimulus.
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PMID:Tyrosine hydroxylase transcription depends primarily on cAMP response element activity, regardless of the type of inducing stimulus. 1503 81

Stress induces tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) gene expression in sympathetic ganglia and adrenal medulla (AM). However, distinct molecular mechanisms appear to regulate these genes in these locations. The elevation of TH mRNA in response to single immobilization stress (IMO) in AM is robust, but transient, while the induction of TH and DBH mRNAs in sympathetic ganglia is slower and more long lasting. Injections of adrenocorticotropic hormone (ACTH) elicited induction of TH and DBH gene expression in rat sympathetic ganglia, but not in AM. The superior cervical (SCG) and stellate (StG) ganglia, but not AM, were found to express mRNA for the MC-2 receptor, the major ACTH responsive receptor in adrenal cortex. IMO led to increase in MC-2 receptor mRNA levels in SCG. Thus, ACTH, via the MC-2 receptor, may be directly involved in the stress-elicited regulation of norepinephrine biosynthesis in sympathetic ganglia. The signaling pathways triggered by IMO differed in these locations. In AM, IMO triggered activation of the MAP kinase, JNK, and induction of AP1 factors, Egr1 and phosphorylation of CREB. In contrast in the SCG, with IMO we did not observe changes in JNK and little binding to the AP1 motif of the TH promoter. However, there was an increase in CREB binding to the CRE site of the TH promoter. The results reveal differential mechanisms of regulation of catecholamine biosynthetic enzymes by stress in two components of the sympathoadrenal system and should provide basis for possible selective pharmacologic interventions.
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PMID:Molecular regulation of gene expression of catecholamine biosynthetic enzymes by stress: sympathetic ganglia versus adrenal medulla. 1524 Mar 92

Testes determining factor Sry is encoded by the Sry locus on the Y chromosome and may be involved in the regulation of blood pressure. Here we tested the hypothesis that Sry regulates transcription of tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of catecholamines. Sry was found to be expressed in catecholaminergic regions, in male but not female rats. Co-transfection of PC12 cells with expression vector for Sry and the reporter construct [p5'TH(-773/+27)/Luc], containing 773 of the proximal nucleotides of the TH promoter directing luciferase reporter activity, led to elevation of reporter activity. The reporter activity of a shorter construct [p5'TH(-272/+27)/Luc] lacking putative Sry sites also responded to Sry. However, mutation of the AP1 site in the TH promoter greatly reduced induction by Sry, indicating that the regulation is primarily at this motif. The remaining, significantly increased expression with the mutated TH promoter construct may reflect Sry function at other sites in addition to the AP1 motif. These results reveal that Sry can regulate TH transcription and suggest that this may be one of the mechanisms of Sry mediated regulation of catecholamine biosynthesis in catecholaminergic neurons in males.
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PMID:Regulation of tyrosine hydroxylase gene transcription by Sry. 1546 65

Previous studies identified nicotine and angiotensin receptors as major trans-synaptic and hormonal inputs controlling activities and mRNA levels of the catecholamine biosynthetic enzymes in adrenal medullary (AM) cells. The purpose of this study was to further explore the molecular mechanisms underlying these modes of regulations. Incubation of cultured bovine AM cells with nicotine or a stable analog of angiotensin II, sar1-angiotensin II, increased synthesis of tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNAs (2- to 3-fold), suggesting transcriptional activation of these genes. No effects of nicotine or sar1-angiotensin II on TH and PNMT mRNA levels could be demonstrated in cells treated with cycloheximide or puromycin, suggesting regulation by inducible proteins. However, translational inhibitors produced small increases in basal TH mRNA levels (1.5- to 1.9-fold), indicating that repressor-like mechanisms participate in the regulation of the TH gene. Sequence analysis of the bovine TH promoter (1.6 kb) revealed the presence of several putative regulatory elements including four nonidentical AP1-like sites, potential targets for c-Fos/c-Jun/AP1 regulation. Formation of sequence-specific complexes between nuclear proteins and five fragments of the TH promoter (200-400 nt) was demonstrated by gel mobility shift assay (one to three complexes per fragment). Binding of proteins to three promoter fragments containing single AP1-like elements was antagonized by an oligodeoxynucleotide-containing AP1 consensus sequence (oligo-AP1), but not by other unrelated DNA sequences. Oligo-AP1 inhibited the formation of one or two complexes with individual DNA fragments. These observations suggest formation of different AP1-like complexes on individual promoter fragments. c-Fos antibody inhibited the formation of three oligo-AP1-displaceable complexes. The formation of the majority of retarded bands, including all AP1-like complexes, was increased by incubation of cells with sar1-angiotensin II or nicotine. Western analysis demonstrated the presence of c-Fos (p54), c-Jun (p36-38), and several c-Fos- and c-Jun-related antigens in control and stimulated AM cells. Sar1-angiotensin II and nicotine increased steady-state levels of c-Fos (1.5- to 2-fold) and c-fos mRNA (10- to 14-fold) and the levels of several c-Fos-related antigens (FRA) (2- to 7-fold). Some of FRA showed differential regulation by angiotensin II and nicotinic receptors. The levels of p36-38 c-Jun and c-jun mRNA were increased by sar1-angiotensin II (2- to 5-fold) and were less affected by nicotine. In conclusion, our results suggest transcriptional regulation of the TH gene by angiotensin II and nicotinic receptors, through partially different nuclear pathways. The regulation may involve multiple target sites in the TH promoter, inducible proteins, AP1-like factors, c-Fos, and c-Fos-related antigens.
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PMID:Neural and hormonal regulation of the tyrosine hydroxylase gene in adrenal medullary cells: Participation of c-fos and AP1 factors. 1991 71


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