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Query: UNIPROT:P06889 (Mol)
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Differential screening of cDNA libraries was used to detect and prepare probes for mRNAs that are regulated in PC12 rat pheochromocytoma cells by long-term (2-week) treatment with nerve growth factor (NGF). In response to NGF, PC12 cells change from a chromaffin cell-like to a sympathetic-neuron-like phenotype. Thus, one aim of this study was to identify NGF-regulated mRNAs that may be associated with the attainment of neuronal properties. Eight NGF-regulated mRNAs are described. Five of these increase 3- to 10-fold and three decrease 2- to 10-fold after long-term NGF exposure. Each mRNA was characterized with respect to the time course of the NGF response, regulation by agents other than NGF, and rat tissue distribution. Partial sequences of the cDNAs were used to search for homologies to known sequences. Homology analysis revealed that one mRNA (increased 10-fold) encodes the peptide thymosin beta 4 and a second mRNA (decreased 2-fold) encodes tyrosine hydroxylase. Another of the increased mRNAs was very abundant in sympathetic ganglia, barely detectable in brain and adrenals, and undetectable in all other tissues surveyed. One of the decreased mRNAs, by contrast, was very abundant in the adrenals and nearly absent in the sympathetic ganglia. With the exception of fibroblast growth factor, which is the only other agent known to mimic the differentiating effects of NGF on PC12 cells, none of the treatments tested (epidermal growth factor, insulin, dibutyryl cyclic AMP, dexamethasone, phorbol ester, and depolarization) reproduced the regulation observed with NGF. These and additional findings suggest that the NGF-regulated mRNAs may play roles in the establishment of the neuronal phenotype and that the probes described here will be useful to study the mechanism of action of NGF and the development and differentiation of neurons.
Mol Cell Biol 1987 Sep
PMID:Identification and characterization of mRNAs regulated by nerve growth factor in PC12 cells. 367 Mar 9

Loss of responsiveness of the neuronal-type nicotinic acetylcholine receptor (nAChR) on PC12 cells, a cell line derived from a rat pheochromocytoma, was induced by exposure to carbamylcholine (carbachol). Nicotinic receptor function was assessed by carbachol-induced 22Na+ uptake. We found that, in addition to classically described desensitization, a second process occurs which results in a nonrecoverable loss of nAChR activity. This second process, which we have labeled inactivation, has a slower onset than the classically described desensitization (t1/2 = 14.7 min for inactivation and 0.78 min for desensitization at 1 mM carbachol). Inactivation could not be explained by inadequate washing, a loss of electrochemical driving force, or a loss of cell viability. The onset of inactivation is dependent on the concentration of desensitizing ligand and is blocked by nicotinic antagonists. No recovery of the loss of activity from inactivation was observed even after 2 hr of incubation in recovery buffer. Inactivation does not appear to require formation of a desensitized state since desensitization was reduced in the absence of Ca2+ whereas inactivation was not affected by the absence of Ca2+. The mechanism which underlies inactivation remains to be determined; however, it is possible that inactivation is the first step in nAChR down-regulation and it may also explain previous observations of rapid and prolonged tolerance to the effects of nicotinic agonists.
Mol Pharmacol 1986 Jul
PMID:Two components of carbamylcholine-induced loss of nicotinic acetylcholine receptor function in the neuronal cell line PC12. 372 45

Transfection into cultured cell lines was used to investigate the transcriptional regulation of the human cardiac actin gene. We first demonstrated that in both human heart and human skeletal muscle, cardiac actin mRNAs initiate at the identical site and contain the same first exon, which is separated from the first coding exon by an intron of 700 base pairs. A region of 485 base pairs upstream from the transcription initiation site of the human cardiac actin gene directs high-level transient expression of the bacterial chloramphenicol acetyltransferase gene in differentiated myotubes of the mouse C2C12 muscle cell line, but not in mouse L fibroblast or rat PC-G2 pheochromocytoma cells. Deletion analysis of this region showed that at least two physically separated sequence elements are involved, a distal one starting between -443 and -395 and a proximal one starting between -177 and -118, and suggested that these sequences interact with positively acting transcriptional factors in muscle cells. When these two sequence elements are inserted separately upstream of a heterologous (simian virus 40) promoter, they do not affect transcription but do give a small (four- to fivefold) stimulation when tested together. Overall, these regulatory regions upstream of the cap site of the human cardiac actin gene show remarkably high sequence conservation with the equivalent regions of the mouse and chick genes. Furthermore, there is an evolutionarily conserved repeated motif that may be important in the transcriptional regulation of actin and other contractile protein genes.
Mol Cell Biol 1986 Jun
PMID:Upstream regions of the human cardiac actin gene that modulate its transcription in muscle cells: presence of an evolutionarily conserved repeated motif. 378 89

A nearly full-length cDNA clone isolated from the rat pheochromocytoma cell line, PC12, revealed extensive nucleotide sequence similarity between the rat cDNA and the Drosophila melanogaster hsp70 gene. The rat recombinant clone encodes a 71,000-dalton protein that is 70% identical with the dipteran hsp70 protein. Remarkably, a truncated segment of this cDNA clone was originally isolated by immunoreactivity with antisera raised to catecholamine-synthesizing enzymes, suggesting that this heat shock protein and these catecholamine enzymes shared antigenic determinants. The rat hsp70-related mRNA is responsible for the production of a constitutive hsp70 protein, because it is present in abundant amounts in various tissues at normal growth temperatures and is only minimally induced by hyperthermia. The rat hsp70-related sequence is part of a multigene family that extends across species to mice and humans.
Mol Cell Biol 1985 Dec
PMID:Constitutively expressed rat mRNA encoding a 70-kilodalton heat-shock-like protein. 393 19

meta-Iodobenzylguanidine, an adrenal imaging agent used for the scintigraphic detection of human pheochromocytoma, is a substrate for the monoamine uptake system of chromaffin granules. It is accumulated by bovine chromaffin granule membrane vesicles in the presence of ATP, and it can be released by an osmotic shock. The uptake is dependent upon the generation of an H+-electrochemical gradient by an ATP-dependent H+ pump since it is blocked by an H+ ionophore and since meta-iodobenzylguanidine uptake can be driven by imposing an artificial pH gradient (inside acidic) on the membrane vesicles. The transport is saturable and its Km value (2.0 microM at pH 8.0) is similar to that of noradrenaline (5.3 microM). Transport occurs through the monoamine transporter since it is blocked by the same inhibitors, tetrabenazine and reserpine, and also by the transporter substrates noradrenaline and serotonin. Noradrenaline inhibits meta-iodobenzylguanidine uptake competitively (Ki = 13 microM). In addition, meta-iodobenzylguanidine displaces dihydrotetrabenazine and reserpine from their binding sites on chromaffin granule membranes. It is thus likely that, after in vivo administration, [131I] meta-iodobenzylguanidine is ultimately stored in chromaffin granules and that it is translocated by the monoamine transporter.
Mol Pharmacol 1986 Mar
PMID:Uptake of meta-iodobenzylguanidine by bovine chromaffin granule membranes. 395 33

Pheochromocytoma cells, clone PC12, possess neuronal nicotinic acetylcholine (ACh) receptors which can be activated by an agonist to produce a transient transmembrane cation flux similar to that seen with neuromuscular nicotinic ACh receptors. We have observed that these neuronal nicotinic ACh receptors are subject to long term regulation by the cholinergic agonist carbamoylcholine (carbachol). Receptor function was measured by agonist-induced uptake of 86Rb+ into the cells. Chronic exposure to concentrations of carbachol that caused receptor activation induced an adaptation (down-regulation) of the receptors, seen as a decrease in the responsiveness of the cells to a subsequent exposure to carbachol. The extent of the decreased responsiveness was proportional to the concentration of carbachol between 50 microM and 10 mM and was distinct from acute receptor desensitization. The concentrations of carbachol that caused down-regulation were greater than those that caused maximum receptor activation, but were similar to those that greatly enhanced desensitization. This suggested that promotion of the desensitized state of the receptor could be the true stimulus for down-regulation. Adaptation was observed initially after several hours of exposure and maximally within about 7 days. Recovery from the down-regulated state required several days of growth in the absence of carbachol. Treatment with the antagonist mecamylamine did not cause a similar change in the responsiveness of the cells. However, concurrent exposure to carbachol and mecamylamine prevented down-regulation. Therefore, it appeared that receptor activation was necessary for regulation to occur. Comparison of the cellular responses of chronically treated and control cells to acute stimulation with carbachol supported the hypothesis that the mechanism for this down-regulation in PC12 cells was a decrease in the number of functional ACh receptors.
Mol Pharmacol 1985 Apr
PMID:Agonist-induced regulation of the neuronal nicotinic acetylcholine receptor of PC12 cells. 398 88

The repeated administration of haloperidol or fenfluramine for several days led to an increase of enkephalin content in specific brain areas. In order to characterize the nature of the dynamic changes underlying this increase, we measured the content of proenkephalin mRNA (PE-mRNA), of high molecular weight (HMW) enkephalin precursors, and of low molecular weight enkephalin peptides (LMW) in various brain areas. To measure PE-mRNA, we hybridized the specific mRNA with a [32P]cDNA probe for human pheochromocytoma PE. HMW and LMW enkephalin content was measured by radioimmunoassay after separation of the immunoreactive peaks by Bio-Gel P-2 column chromatography and enzymatic digestion of the precursors. Haloperidol treatment increased enkephalins, the precursor, and PE-mRNA content in the striatum, suggesting that this drug might increase enkephalin steady state by increasing transcription, translation, or both processes. In contrast, fenfluramine increased hypothalamic and striatal enkephalin content by preferentially reducing neuropeptide utilization or decreasing its catabolism without changing its synthesis.
Mol Pharmacol 1985 Jul
PMID:Use of mRNA hybridization and radioimmunoassay to study mechanisms of drug-induced accumulation of enkephalins in rat brain structures. 402 99

PC12 cells, derived from a rat pheochromocytoma, were mutagenized and selected in media containing agents known to elevate intracellular concentrations of cyclic AMP (cAMP). More than 40 clones were isolated by selection with cholera toxin or 2-chloroadenosine or both. The variants that were deficient in accumulating cAMP were obtained by using a protocol in which 1 microM 8-bromo-cAMP was included in addition to the agonist. Certain of these variants were partially characterized with respect to the site of altered cAMP metabolism. The profiles of adenylate cyclase activity responsiveness of certain variants to guanosine-5'-(beta, gamma-imido) triphosphate and to forskolin resembled those of UNC and cyc phenotypes of S49 lymphoma cells, which are functionally deficient in the GTP-sensitive coupling protein, Ns. Other variants were characterized by increased cyclic nucleotide phosphodiesterase activity at low substrate concentration. Diverse morphological traits were observed among the variants, but it was not possible to assign them to a particular cAMP phenotype. Two revertants of a PC12 mutant were isolated and observed to have regained a cellular cAMP response to 2-chloroadenosine and to forskolin. It is hoped that these PC12 mutants will have utility for defining cAMP-mediated functions, including any links to the action of nerve growth factor, in cells derived from the neural crest.
Mol Cell Biol 1984 Oct
PMID:Mutants of PC12 cells with altered cyclic AMP responses. 609 39

Incubation of pheochromocytoma cells with 56 mM K+ or with cholera toxin increases the conversion of [14C]tyrosine to [14C]catecholamines (Chalfie, M., Settipani, L., and Perlman, R. L. (1979) Mol. Pharmacol. 15, 263-270). We have now measured the tyrosine content and the rate of dihydroxyphenylalanine production in these cells. Incubation with 56 mM K+ or with cholera toxin increases the rate of dihydroxyphenylalanine production but decreases the tyrosine content of the cells. We have also measured the uptake of tyrosine into pheochromocytoma cells. The rate of tyrosine uptake is more than 1 order of magnitude greater than the rate of dihydroxyphenylalanine production. Moreover, tyrosine uptake is not affected by cholera toxin and is decreased by approximately 30% in media that contain 56 mM K+. These results provide direct evidence that tyrosine 3-monooxygenase regulates catecholamine synthesis in pheochromocytoma cells and that incubation with 56 mM K+ or with cholera toxin causes the activation of this enzyme in these cells.
 ...
PMID:Tyrosine 3-monooxygenase regulates catecholamine synthesis in pheochromocytoma cells. 610 63

We have extended our analysis of human tumors using antibodies specific for each of the five types of intermediate filaments to neuroblastoma, ganglioneuroblastoma, pheochromocytoma, ependymoblastoma, and alveolar soft part sarcoma. Tumor cells in the three cases of neuroblastoma, as well as in the single case of alveolar soft part sarcoma, did not react positively with sera directed against any of the five intermediate filament types. We suppose, therefore, that neuroblastoma at least may be derived from a cell type - possibly present in peripheral neurones - which in vivo has very few or no intermediate filaments. In ganglioneuroblastoma and in pheochromocytoma the tumor cells were positive when tested with antibodies directed against neurofilaments and negative with those directed against other intermediate filament types. The ependymoblastoma was positive when tested with antibodies directed against glial fibrillary acidic protein (GFA) and negative when tested with antibodies against other intermediate filament types. Use of antibodies to the different intermediate filament types appears to be a valid way in which to classify tumors, and so far the data presented here and elsewhere support the hypothesis that tumor cells retain the intermediate filament type typical of their cell of origin. Wider use of these sera would seem particularly useful in cases such as neuroblastoma, rhabdomyosarcoma or lymphoma where diagnosis is currently difficult using conventional histological stains.
Virchows Arch B Cell Pathol Incl Mol Pathol 1982 Aug
PMID:Various sympathetic derived human tumors differ in neurofilament expression. Use in diagnosis of neuroblastoma, ganglioneuroblastoma and pheochromocytoma. 612 32


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