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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of the thyroid hormones by the thyroid tissue is regulated by thyrotropin (TSH). TSH, through cAMP, enhances all steps of T3 and T4 synthesis, among which transcription of the genes encoding the precursor protein, thyroglobulin (TG) and the enzyme responsible for the iodination and coupling mechanisms, thyroperoxidase (TPO). Run-on transcription assays show that the kinetics of TG gene transcriptional activation by cAMP is slow (8 to 16 hours) in dog thyrocytes in primary culture, while it is rapid (1 hour) in dog thyroid slices. Activation is sensitive to cycloheximide, reflecting the need for ongoing protein synthesis. In contrast, stimulation of TPO gene transcription is rapid in both experimental systems and is not inhibited in the presence of cycloheximide. It is concluded that different regulatory mechanisms are implicated in the control of Tg and TPO gene transcription by cAMP. However, the stimulation of TG and TPO gene transcription are equally suppressed by inhibition of cAMP-dependent protein kinase, which suggests that both regulatory mechanisms involve protein phosphorylation.
...
PMID:Distinct transcriptional effects of cAMP on 2 thyroid specific genes: thyroperoxidase and thyroglobulin. 217 Feb 61

The dog thyrocyte I- trapping activity and the expression of the genes coding for dog thyrocyte thyroglobulin or thyroid peroxidase are enhanced by TSH through the cAMP cascade and reduced by mitogens such as epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol 13-acetate (TPA). In this work, we investigated whether H2O2 generation (a limiting step of thyroid hormone synthesis) is modulated by chronic treatment of the thyrocyte with TSH or mitogens such as EGF or TPA. We observed that both basal and carbachol- or ionomycin-stimulated H2O2 generation by the dog thyrocyte were concentration and time dependently enhanced by prolonged (12- to 72-h) exposure to TSH. This effect was reproduced by agents that increase the dog thyrocyte cAMP level or that mimic this increase. It was abolished when protein or RNA synthesis was inhibited. By contrast, EGF and TPA concentration and time dependently antagonized the effect of TSH. In addition, chronic exposure to EGF reduced both basal and carbachol- or ionomycin-stimulated H2O2 generation. The effect of TPA was reproduced by another protein kinase-C activating phorbol ester, phorbol dibutyrate, but not by beta-phorbol, an inactive phorbol ester. Modulation of dog thyrocyte H2O2 generation by chronic exposure to TSH or to the mitogens EGF and TPA was totally parallel to the modulation of their 125I- uptake. Taken together our results suggest that H2O2 generation (or at least one of its constituents) is a differentiation characteristic of the dog thyrocyte under tonic control of TSH through the cAMP cascade as iodide transport, thyroid peroxidase, and thyroglobulin.
...
PMID:Tonic modulation of dog thyrocyte H2O2 generation and I- uptake by thyrotropin through the cyclic adenosine 3',5'-monophosphate cascade. 786 6

The chimeric chloramphenicol acetyltransferase (CAT) construct, pTRCAT5'-199, containing the TSH receptor (TSHR) minimal promoter, -199 to -39 base pairs (bp), exhibits the thyroid specificity and TSH/cAMP autoregulation evident in TSHR gene expression. The present report shows that a cis-acting element between -189 and -175 bp, which binds thyroid transcription factor-1 (TTF-1), is involved in both activities. The 22 bp between -199 and -178 contains a positive element important for expression of the TSHR minimal promoter in rat FRTL-5 thyroid cells. DNAase I footprinting shows that extracts from functioning FRTL-5, but not non-functioning FRT thyroid or Buffalo rat liver (BRL) cells, protect a region between -189 and -175 bp. The protection is duplicated by TTF-1, and the protected element has only a two-base mismatch from the consensus TTF-1 element identified in the thyroglobulin (TG) and thyroid peroxidase minimal promoters. Gel mobility shift analyses reveal that FRTL-5 thyroid cell nuclear extracts form a specific protein/DNA complex with this region, which is prevented by the TTF-1 binding element from the TG promoter; FRT and BRL cell nuclear extracts do not have TTF-1 and do not form this complex. A role for the TSHR/TTF-1 binding element in thyroid-specific expression of the TSHR gene is evidenced as follows. Overexpression of TTF-1 in FRT or BRL cells, which have no TTF-1, increased the activity of pTRCAT5'-199, but not pTRCAT5'-177, which has no TTF-1 binding element. A nonsense mutation of the TTF-1 binding element eliminated TTF-1-induced activation of TSHR promoter activity in FRT or BRL cells and reduced TSHR promoter activity in FRTL-5 thyroid cells. In contrast, mutation of this element to the TTF-1 consensus sequence of the TG or thyroid peroxidase promoter had no significant influence on TSHR promoter activity. The activity of the TSHR/TTF-1 binding element requires a functioning cAMP response element (CRE). Thus, TTF-1 activity is lost when the CRE site is mutated to a nonfunctional, nonpalindromic sequence; it is, in contrast, maximized when CRE activity is maximized by its mutation to a consensus AP1 element. TTF-1 phosphorylation is important for binding and activity. Thus, binding of TTF-1 to the TSHR/TTF-1 element is phosphatase-sensitive and is increased by treating nuclear extracts with the catalytic subunit of protein kinase A. Overexpression of the catalytic subunit of PKA enhances TTF-1-increased activity of the TSHR minimal promoter.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Thyroid-specific expression and cyclic adenosine 3',5'-monophosphate autoregulation of the thyrotropin receptor gene involves thyroid transcription factor-1. 799 32

Effects of anesthetics on thyroidal hydrogen peroxide generating system was studied using porcine thyroid follicles. This system is indispensable in thyroid hormone synthesis and seems also to play an important role in regulation of thyroid hormone release. The results indicated that H2O2 generation was controlled by Ca2+ ion mobilization and protein kinase-C linked signal transduction system. It was also demonstrated that thiopental, halothane, and enflurane had inhibitory effects on H2O2 generation system in thyroid follicle cells, and 50% inhibitory concentrations (IC50) of each anesthetic drug were 60 microM, 2.5% and 4.0%, respectively. Other anesthetic agents, such as local anesthetics and major tranquilizers did not show any inhibitory effects on porcine thyroid peroxidase activity as well as on the regulation of thyroid hormone release. Other than inhaled anesthetic agents, thiopental only is thought to have an antithyroid effects in clinical situation.
...
PMID:[In vitro effects of anesthetics on hydrogen peroxide generating system of the thyroid gland]. 830 32

The conserved structure of the transcription factors of the Pax gene family may reflect functional conservation. We have demonstrated that the human Pax8 transcription factor is organized in several functional domains and contains two regions responsible for its nuclear localization, in addition to an activating region at the carboxy terminus of the protein and an inhibitory region encoded by the exon 9 present only in a splice variant PAX8a. Regions of PAX8 determining the nuclear localization of the PAX8A/lacZ fusions contain short amino acid sequences similar to several described nuclear localization sites (NLS). These NLS were identified in the paired domain and between the octapeptide and the residual homeodomain, respectively. The activating domain is encoded by the exons 10 and 11 and its function is modulated by the adjacent domains encoded by the exons 9 and 12. The domain encoded by exon 9 significantly inhibits the function of the activating domain. Pax8 is expressed in thyroid cells and its product binds promoters of the thyroglobulin and thyroperoxidase genes through its paired domain. Thyroid cell growth and differentiation depend on thyrotropin which, by stimulating cAMP synthesis, activates the cAMP-dependent protein kinase A (PKA). We have investigated a link between thyrotropin stimulation and gene activation by Pax8. Stimulation of cAMP synthesis augments Pax8-specific transcription in thyroid cells, indicating that PKA is involved in Pax8 activation. Cotransfection of GAL4/PAX8 fusions and the catalytic subunit of PKA in A126, a PKA-deficient derivative of the PC12 pheochromocytoma cell line, synergistically activates the GAL4-specific reporter, suggesting the activating domain of PAX8 is dependent upon the catalytic subunit of the PKA. We propose that this dependence is due to a hypothetical adaptor which forms a target for PKA and interacts with the activating domain of PAX8. We show that PAX8 isolated from the thyroid cell line FTRL5 is a phosphoprotein in which phosphorylation is not dependant on cAMP pathway activation. Our results suggest that Pax8 is part of the cAMP signaling pathway and mediates thyrotropin-dependent gene activation in thyroid cells. Investigation of the PAX8 expression in a panel of Wilms' tumors shows a striking correlation between the expression of PAX8 and another transcription factor, WT1, indicating that these two genes may interact in vivo.
...
PMID:Determination of functional domains of the human transcription factor PAX8 responsible for its nuclear localization and transactivating potential. 928 8

Thyrotropin (TSH), via a cyclic AMP (cAMP)-dependent pathway, induces cytoplasmic retractions, proliferation, and differentiation expression in dog thyroid cells. The role of cAMP-dependent protein kinase (PKA) in the induction of these events was assessed by microinjection into living cells. Microinjection of the heat-stable inhibitor of PKA (PKI) inhibited the effects of TSH, demonstrating that activation of PKA was required in this process. Overexpression of the catalytic (C) subunit of PKA brought about by microinjection of the expression plasmid pC alpha ev or of purified C subunit itself was sufficient to mimic the cAMP-dependent cytoplasmic changes and thyroperoxidase mRNA expression but not to induce DNA synthesis and thyroglobulin (Tg) expression. The cAMP-dependent morphological effect was not observed when C subunit was coinjected with the regulatory subunit (RI or RII subunit) of PKA. To mimic the cAMP-induced PKA dissociation into free C and R subunits, the C subunit was coinjected with the regulation-deficient truncated RI subunit (RIdelta1-95) or with wild-type RI or native RII subunits, followed by incubation with TSH at a concentration too low to stimulate the cAMP-dependent events by itself. Although the cAMP-dependent morphology changes were still observed, neither DNA synthesis nor Tg expression was stimulated in these cells. Taken together, these data suggest that in addition to PKA activation, another cAMP-dependent mechanism could exist and play an important role in the transduction of the cAMP signal in thyroid cells.
...
PMID:Activation of cyclic AMP-dependent kinase is required but may not be sufficient to mimic cyclic AMP-dependent DNA synthesis and thyroglobulin expression in dog thyroid cells. 934 36

Cytokine receptors of the hematopoietic receptor superfamily lack intrinsic tyrosine kinase domains for the intracellular transmission of their signals. Instead all members of this family associate with Jak family nonreceptor tyrosine kinases. Upon ligand stimulation of the receptors, Jaks are activated to phosphorylate target substrates. These include STAT (signal transducers and activators of transcription) proteins, which after phosphorylation translocate to the nucleus and modulate gene expression. The exact role of the Jak-STAT pathway in conveying growth and differentiation signals remains unclear. Here we describe a deletion mutant of the thrombopoietin receptor (c-mpl) that has completely lost the capacity to activate Jaks and STATs but retains its ability to induce proliferation. This mutant still mediates TPO-induced phosphorylation of Shc, Vav, mitogen-activated protein kinase (MAPK) and Raf-1 as well as induction of c-fos and c-myc, although at somewhat reduced levels. Furthermore, we show that both wild-type and mutant receptors activate phosphatidylinositol (PI) 3-kinase upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is inhibited in the presence of the PI 3-kinase inhibitor wortmannin. These results demonstrate that the Jak-STAT pathway is dispensable for the generation of mitogenic signals by a cytokine receptor.
...
PMID:The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. 939 63

Follicular thyroglobulin (TG) decreases expression of the thyroid-restricted transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, thereby suppressing expression of the sodium iodide symporter, thyroid peroxidase, TG, and thyrotropin receptor genes (Suzuki, K., Lavaroni, S., Mori, A., Ohta, M., Saito, J., Pietrarelli, M., Singer, D. S., Kimura, S., Katoh, R., Kawaoi, A. , and Kohn, L. D. (1997) Proc. Natl. Acad. Sci. U. S. A. 95, 8251-8256). The ability of highly purified 27, 19, or 12 S follicular TG to suppress thyroid-restricted gene expression correlates with their ability to bind to FRTL-5 thyrocytes and is inhibited by a specific antibody to the thyroid apical membrane asialoglycoprotein receptor (ASGPR), which is related to the ASGPR of liver cells. Phosphorylating serine/threonine residues of TG, by autophosphorylation or protein kinase A, eliminates TG suppression and enhances transcript levels of the thyroid-restricted genes 2-fold in the absence of a change in TG binding to the ASGPR. Follicular TG suppression of thyroid-restricted genes is thus mediated by the ASPGR on the thyrocyte apical membrane and regulated by a signal system wherein phosphorylation of serine/threonine residues on the bound ligand is an important component. These data provide a hitherto unsuspected role for the ASGPR in transcriptional signaling, aside from its role in endocytosis. They establish a functional role for phosphorylated serine/threonine residues on the TG molecule.
...
PMID:Follicular thyroglobulin (TG) suppression of thyroid-restricted genes involves the apical membrane asialoglycoprotein receptor and TG phosphorylation. 1045 90

Monolayer primary cultures of thyroid cells produce, in the presence of insulin, a cytosolic inhibitor of thyroid peroxidase (TPO), lacto peroxidase (LPO), horseradish peroxidase (HRPO) and glutathione peroxidase (GPX). The inhibitor, localized in the cytosol, is thermostable and hydrophylic. Its molecular mass is less than 2 kDa. The inhibitory activity, resistant to proteolytic and nucleolytic enzymes, disappears with sodium metaperiodate treatment, as an oxidant of carbohydrates, supporting its oligosaccharide structure. The presence of inositol, mannose, glucose, the specific inhibition of cyclic AMP-dependent protein kinase and the disappearance of peroxidase inhibition by alkaline phosphatase and alpha-mannosidase in purified samples confirms its chemical structure as inositol phosphoglycan-like. Purification by anionic interchange shows that the peroxidase inhibitor elutes like the two subtypes of inositol phosphoglycans (IPG)P and A, characterized as signal transducers of insulin action. Insulin significantly increases the concentration of the peroxidase inhibitor in a thyroid cell culture at 48 h. The addition of both isolated substances to a primary thyroid culture produces, after 30 min, a significant increase in hydrogen peroxide (H2O2) concentration in the medium, concomitantly with the disappearance of the GPX activity in the same conditions. The presence of insulin or anyone of both products, during 48 h, induces cell proliferation of the thyroid cell culture. In conclusion, insulin stimulates thyroid cell division through the effect of a peroxidase inhibitor, as its second messenger. The inhibition of GPX by its action positively modulates the H2O2 level, which would produce, as was demonstrated by other authors, the signal for cell proliferation.
...
PMID:Role of peroxidase inhibition by insulin in the bovine thyroid cell proliferation mechanism. 1520 26

The aim of this work was to investigate the role of cytosolic calcium and calmodulin-dependent systems in the activation of glucose uptake in the human megakaryocytic cell line M07e. Glucose uptake was significantly raised by elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) with thapsigargin, this effect being additive to the activation induced by cytokines (SCF, GM-CSF and TPO) and hydrogen peroxide. Intracellular Ca(2+) chelation by BAPTA decreased basal and activated glucose uptake in a dose-dependent manner. BAPTA reduced the GLUT1 translocation induced by SCF and H(2)O(2), suggesting a major role for Ca(2+) in GLUT1 intracellular trafficking. In the absence of extracellular Ca(2+), 2-aminoethoxydiphenyl-borate (2-APB) abolished the activation of glucose uptake induced by cytokines and H(2)O(2) suggesting an involvement in GLUT1 regulation in responses related to InsP(3)-induced Ca(2+) release. Under our experimental conditions, all the stimuli inducing glucose uptake activation failed to increase [Ca(2+)](c) suggesting that cytosolic Ca(2+) plays a permissive role in the regulation of GLUT1. The calmodulin antagonist W-7 and the inhibitor of Ca(2+)-calmodulin dependent protein kinase II (CAMK II) KN-62 removed the glucose transport activation by all the tested stimuli. These results suggest that in M07e cells calmodulin and CAMKII are involved in GLUT1 stimulation by cytokines and ROS.
...
PMID:Glucose transport activation in human hematopoietic cells M07e is modulated by cytosolic calcium and calmodulin. 1676 11


1 2 Next >>

---