Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0031511 (pheochromocytoma)
14,622 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine hydroxylase purified from rat pheochromocytoma is phosphorylated rapidly by the Ca2+- and phospholipid-dependent protein kinase (protein kinase C) purified from rat or sheep brain. Phosphorylation was stimulated 14-fold by Ca2+ and phosphatidylserine and occurred at a rate comparable with that of the phosphorylation of histone Hl. The phospholipid-dependent protein kinase phosphorylates a single site which is identical to that phosphorylated by cyclic AMP-dependent protein kinase and to the secondary site of phosphorylation by the calmodulin-dependent multiprotein kinase. The implications of these results with respect to the regulation of catecholamine biosynthesis in adrenal medulla are discussed.
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PMID:Characterization of the sites phosphorylated on tyrosine hydroxylase by Ca2+ and phospholipid-dependent protein kinase, calmodulin-dependent multiprotein kinase and cyclic AMP-dependent protein kinase. 285 5

Two clonal cell lines (the pheochromocytoma clone PC-12 and the neuroblastoma clone N1E-115) were used to compare direct and indirect drug effects on tyrosine hydroxylase and dopamine turnover. Both clones contain the cofactor of tyrosine hydroxylase, tetrahydrobiopterin, in sufficient concentrations. 2,4-Diamino-6-hydroxy-pyrimidine (DAO-Pyr), an inhibitor of GTP cyclohydrolase, which is the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, lowers DOPA production indicating that cofactor supply is a limiting factor for catecholamine synthesis. DOPA synthesis in the PC-12 cells can be stimulated by incubation with the natural cofactor tetrahydrobiopterin, but also by its possible precursors sepiapterin and dihydrobiopterin or the analogs methyl-tetrahydropterin and dihydropterin. The regulating enzyme for DOPA synthesis, tyrosine hydroxylase, can be inhibited by certain drugs either directly or indirectly by increasing dopamine concentrations in the cytoplasm after release from its vesicular stores. Using the neuroblastoma clone N1E-115 which lacks DOPA decarboxylase and thus contains only low levels of dopamine the site of action of certain drugs could be determined. Drugs affecting the tyrosine hydroxylase directly (alpha-methyl-para-tyrosine, apomorphine) decreased DOPA production in both clones, while drugs acting via interference with the vesicular stores (reserpine, amphetamine, nigericin) were effective only in the PC-12 cells. After total depletion of dopamine by nigericin at high concentrations or long-term incubation with 3-hydroxybenzyl-hydrazine (NSD 1015), DOPA production increased in the PC-12 cells indicating a usually occurring regulation of tyrosine hydroxylase by cytoplasmic dopamine. Dopamine concentration in the cytoplasm was calculated to be in the range of 1 X 10(-6) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evaluation of neurotropic drug actions on tyrosine hydroxylase activity and dopamine metabolism in clonal cell lines. 285 29

A specific antiserum was used to compare phosphorylation of tyrosine hydroxylase (TH) (EC 1.14.16.2, tyrosine 3-monooxygenase) as regulated by elevated K+ and nerve growth factor (NGF) in cultured PC12 pheochromocytoma cells. Exposure of cultures to either elevated K+ or to NGF significantly enhanced the incorporation of [32P]orthophosphate into TH. The effect of elevated K+ was evident at 10 mM and was maximal by 40-80 mM. Increased phosphorylation of TH was detected at 0.1 nM (3 ng/ml) NGF and reached a maximal level by 0.3-1 nM (10-30 ng/ml) NGF. Elevated K+ showed a biphasic time course of action with one maximum of phosphorylation at about 30 sec of exposure and a second after about 10 min of exposure. In contrast, the NGF effect showed an initial lag of several minutes followed by a monophasic increase in phosphorylation to reach a plateau. Both treatments enhanced TH activity, but in each case the time courses of this did not strictly correlate with that of phosphorylation. The effect of elevated K+ on TH phosphorylation required the presence of extracellular Ca2+ and was suppressed by trifluoperazine (100 microM). N-(6-Aminohexyl)-5-(chloronaphthalene)-1-sulfonamide (W-7) (100 microM), a potent inhibitor of calmodulin activity, also blocked the enhancement of phosphorylation by elevated K+, whereas N-(6-aminohexyl)-1-(naphthalene)sulfonamide (W-5) (100 microM), a less potent analogue of W-7, did not. In contrast to these findings, the increase in TH phosphorylation brought about by NGF did not require extracellular Ca2+, and was only slightly affected by trifluoperazine or W-7. When TH phosphorylated under various conditions (control medium, elevated K+, NGF) was subjected to peptide mapping after exposure to Staphylococcus aureus protease V8, multiple phosphorylated peptides were observed. Elevated K+ and NGF each produced increases in labeling of each of the peptides. However, the relative degree of labeling of different peptides was distinct for each condition. These data suggest that elevated K+ and NGF bring about rapid enhancement of the phosphorylation of TH by means of different mechanisms.
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PMID:Regulation of tyrosine hydroxylase phosphorylation in PC12 pheochromocytoma cells by elevated K+ and nerve growth factor. Evidence for different mechanisms of action. 286 75

Incubation of rat pheochromocytoma PC12 cells with dibutyryl cyclic AMP or 56 mM K+ is associated with increased activity and enhanced phosphorylation of tyrosine hydroxylase in situ. Following incubation of the PC12 cells with 32Pi, rapid isolation of the tyrosine hydroxylase, and tryptic digestion of the enzyme, two distinct 32P-peptides can be identified after paper electrophoresis. 56 mM K+ increases 32Pi incorporation into both of these peptides, whereas dibutyryl cyclic AMP increases 32Pi incorporation into only one of these peptides. The rate of increase in the incorporation of 32Pi into these two peptides in cells treated with 56 mM K+ is similar. The phosphorylation of tyrosine hydroxylase in PC12 cells occurs exclusively on serine residues. These results suggest that tyrosine hydroxylase in PC12 cells is phosphorylated on serine residues at two or more distinct sites after 56 mM K+ -induced depolarization. Since only one of these sites is phosphorylated by cyclic AMP-dependent protein kinase, activation of tyrosine hydroxylase by 56 mM K+ may involve phosphorylation by multiple protein kinases in rat pheochromocytoma PC12 cells.
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PMID:Enhanced phosphorylation of tyrosine hydroxylase at more than one site is induced by 56 mM K+ in rat pheochromocytoma PC12 cells in culture. 286 28

Vasoactive intestinal peptide (VIP) acutely increases tyrosine hydroxylase (TH) activity in cultures of dispersed normal adult rat chromaffin cells and of PC12 rat pheochromocytoma cells. High concentrations of VIP (10 microM) produce about 3-fold increases in TH activity in both cell types. VIP also increases the content of cyclic adenosine 3':5'-monophosphate (cAMP) in PC12 cells. VIP may increase TH activity by promoting the cAMP-dependent phosphorylation of the enzyme. Nerve fibers containing VIP-like immunoreactive material have been reported in the adrenal medulla and in other catecholamine (CA)- storing tissues. This VIPergic innervation may regulate CA synthesis and other cAMP-dependent processes in these tissues.
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PMID:Vasoactive intestinal peptide increases tyrosine hydroxylase activity in normal and neoplastic rat chromaffin cell cultures. 286 99

Rat pheochromocytoma contains a protein kinase activity which remains associated with tyrosine hydroxylase (TH) during its purification. The incorporation of phosphate in TH is observed after incubation of TH with labelled ATP and magnesium without the need for an exogenous protein kinase. This Ca2+ and cAMP-independent kinase activity is different from previously described TH phosphorylating kinases from rat pheochromocytoma and other tissues.
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PMID:[Copurification of tyrosine hydroxylase from rat pheochromocytoma by protein kinase]. 287 47

As reported previously [Vulliet et al. (1985) FEBS Lett. 182 335-339], tyrosine hydroxylase purified from rat pheochromocytoma is phosphorylated at an identical site (site A) by cyclic AMP-dependent protein kinase, the calmodulin-dependent multiprotein kinase and protein kinase C, while the calmodulin-dependent multiprotein kinase also phosphorylates another unique site (site C). Preparations of tyrosine hydroxylase purified from this source are also contaminated with traces of a fourth protein kinase which phosphorylates another unique site (site E). We have isolated tryptic peptides containing each of these sites and determined their amino acid sequences. By comparison of these data with the known cDNA sequence for rat tyrosine hydroxylase, we have been able to identify these sites as Ser-8 (site E), Ser-19 (site C), and Ser-40 (site A). In some preparations of tyrosine hydroxlyase, cyclic AMP-dependent protein kinase also phosphorylated a secondary site which was identified as ser-153. All of these phosphorylation sites are in the amino-terminal region, where there is no significant homology with the closely related enzyme, phenylalanine hydroxylase. Our data also establish that the initiator methionine is removed by post-translational processing to leave pro-2 as the amino-terminus of the mature protein. The significance of these results for the mechanism of action of extracellular signals on catecholamine biosynthesis is discussed.
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PMID:Identification of four phosphorylation sites in the N-terminal region of tyrosine hydroxylase. 287 40

The possibility of employing PC12 pheochromocytoma cells for transplantation into the rat brain as a substitute for adrenal chromaffin cells was examined. Cultured PC12 cells were implanted into the striatum of rats and examined after one day to 20 weeks by fluorescence histochemistry and immunocytochemical staining for tyrosine hydroxylase and a surface antigen of PC12 cells. Between 800 and 3000 cells survived the implantation procedure and persisted relatively unchanged for about one week. Long-term survival of small numbers of PC12 cells was observed in nine of 14 animals, although the number of surviving cells was reduced after 7.5-20 weeks as compared to earlier time periods. By 14-20 weeks after implantation, most of the remaining cells had developed processes. In other animals, there appeared to have been an initial large increase in the number of cells, followed by complete death of the graft. In many of these animals with no surviving cells, large deposits of hemosiderin were found at the implantation site, an apparent residue of earlier tumor growth. Thus in some animals, the number of PC12 cells apparently increased initially, but in these animals the graft was ultimately rejected. In other animals, small numbers of PC12 cells survived for up to 20 weeks, and many of these cells eventually developed neurite-like processes. Continued uncontrolled tumor growth was not observed.
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PMID:Properties of PC12 pheochromocytoma cells transplanted to the adult rat brain. 287 97

Incubation of rat pheochromocytoma PC12 cells with the calcium ionophore, A23187 (10(-5) M), 56 mM K+, or dibutyryl cAMP (2 mM) is associated with increased activity and enhanced phosphorylation of tyrosine hydroxylase in the cells. Both the activation and the increased phosphorylation of tyrosine hydroxylase produced by A23187 and 56 mM K+ are dependent on the presence of extracellular calcium, whereas similar effects produced by dibutyryl cAMP are independent of calcium. The effects of 56 mM K+ plus dibutyryl cAMP or A23187 plus dibutyryl cAMP on the activation and phosphorylation of tyrosine hydroxylase are additive. In contrast, the effects of 56 mM K+ plus A23187 on either the activation or the phosphorylation of the enzyme are not additive. Following stimulation of intact PC12 cells with 32Pi, in order to label ATP stores, and tryptic digestion of the phosphorylated enzyme, separation of the tryptic phosphopeptides by high pressure liquid chromatography yields four distinct 32P-peptide peaks. Incubation of the cells in the presence of either 56 mM K+ or A23187 is associated with increased 32Pi incorporation into three peptides whereas, in the presence of dibutyryl cAMP, increased 32Pi incorporation is observed in only one of these peptides. When tyrosine hydroxylase purified from rat pheochromocytoma tumor is incubated in vitro with [gamma-32P]ATP and either cAMP-dependent or calcium/calmodulin-dependent protein kinase under appropriate conditions, increased phosphorylation of tyrosine hydroxylase is observed. However, even though in vitro phosphorylation by cAMP-dependent protein kinase is associated with activation of tyrosine hydroxylase, in vitro phosphorylation by calcium/calmodulin-dependent protein kinase does not lead to activation of the enzyme. Tryptic digestion of tyrosine hydroxylase phosphorylated by calcium/calmodulin-dependent protein kinase yields three distinct 32P-peptide peaks, which are identical to those phosphorylated by treatment of intact PC12 cells with either high K+ or A23187. In contrast, cAMP-dependent protein kinase phosphorylates only one peptide, which is identical to that phosphorylated by treatment of the intact cells with dibutyryl cAMP. These results indicate that tyrosine hydroxylase is activated and phosphorylated at multiple sites in PC12 cells exposed to 56 mM K+ or A23187. The results suggests that the in situ phosphorylation of these sites is catalyzed by calcium/calmodulin-dependent protein kinase; however, phosphorylation by this protein kinase is not sufficient to activate the enzyme.
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PMID:Phosphorylation of tyrosine hydroxylase on at least three sites in rat pheochromocytoma PC12 cells treated with 56 mM K+: determination of the sites on tyrosine hydroxylase phosphorylated by cyclic AMP-dependent and calcium/calmodulin-dependent protein kinases. 287 91

When rat pheochromocytoma PC18 cells are exposed to the cyclic AMP analog, 8-bromocyclic AMP, and/or the synthetic glucocorticoid, dexamethasone, there is a marked increase in the level of a single RNA species that hybridizes to the recombinant plasmid pTH.4, which contains sequences complementary to the RNA coding for tyrosine hydroxylase. This RNA species is 1800-1900 nucleotides in length and is presumably identical to an RNA species of similar size, isolated from rat pheochromocytoma PC8b cells and shown to code for tyrosine hydroxylase. Using RNA dot hybridization to quantitate the relative level of this tyrosine mRNA species, time course studies show that this mRNA increases relatively rapidly in PC18 cells treated with either 8-bromocyclic AMP or dexamethasone. A new steady state level of tyrosine hydroxylase mRNA is achieved after 6 hr or 12-24 hr of treatment with either 8-bromocyclic AMP or dexamethasone, respectively. The changes in the level of the mRNA slightly precede the changes in the rate of synthesis of tyrosine hydroxylase in cells treated with these inducing agents. After 24 hr of treatment with either 8-bromocyclic AMP or dexamethasone, the increases in the level of tyrosine hydroxylase mRNA are identical to the increases in the rate of synthesis of the enzyme in the cells. In cells treated simultaneously with both 8-bromocyclic AMP and dexamethasone, the increases in the enzyme level and rate of synthesis of tyrosine hydroxylase are approximately equal to the sum of the increases in these parameters observed in cells treated with either inducing agent alone. In contrast, there is not an additive increase in the level of tyrosine hydroxylase mRNA in cells treated with both inducing agents. This lack of an additive increase in mRNA for tyrosine hydroxylase is observed in total cellular RNA samples or in cytoplasmic RNA samples. Our results suggest that in cells exposed to elevated levels of either cyclic AMP or glucocorticoids, tyrosine hydroxylase is induced by a mechanism which increases the level of its mRNA, resulting in an increased rate of synthesis of the enzyme. However, in cells exposed to elevated levels of both cyclic AMP and dexamethasone, tyrosine hydroxylase enzyme levels are regulated by multiple mechanisms, one of which regulates the rate of synthesis of the enzyme without affecting the level of its mRNA.
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PMID:Induction of mRNA for tyrosine hydroxylase by cyclic AMP and glucocorticoids in a rat pheochromocytoma cell line: evidence for the regulation of tyrosine hydroxylase synthesis by multiple mechanisms in cells exposed to elevated levels of both inducing agents. 287 92


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