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)

We established the cis-acting elements which mediate cAMP responsiveness of the human growth hormone (hGH) gene in transiently transfected rat anterior pituitary tumor GC cells. Analysis of the intact hGH gene or hGH 5'-flanking DNA (5'-FR) coupled to the hGh cDNA or chloramphenicol acetyltransferase or luciferase genes, indicated that cAMP primarily stimulated hGH promoter activity. Cotransfection of a protein kinase A inhibitory protein cDNA demonstrated that the cAMP response was mediated by protein kinase A. Mutational analysis of the hGH promoter identified two core cAMP response element motifs (CGTCA) located at nucleotides -187/-183 (distal cAMP response element; dCRE) and -99/-95 (proximal cAMP response element; pCRE) and a pituitary-specific transcription factor (GHF1/Pit1) binding site at nucleotides -123/-112 (dGHF1) which were required for cAMP responsiveness. GHF1 was not a limiting factor, since overexpression of GHF1 in cotransfections increased basal but not forskolin induction levels. Gel shift analyses indicated that similar, ubiquitous, thermostable protein(s) specifically bound the pCRE and dCRE motifs. The CGTCA motif-binding factors were cAMP response element binding protein (CREB)/activating transcription factor-1 (ATF-1)-related, since the DNA-protein complex was competed by unlabeled CREB consensus oligonucleotide, specifically supershifted by antisera to CREB and ATF-1 but not ATF-2, and was bound by purified CREB with the same relative binding affinity (pCRE < dCRE < CREB) and mobility as the GC nuclear extract. UV cross-linking and Southwestern blot analyses revealed multiple DNA-protein interactions of which approximately 100- and approximately 45-kDa proteins were predominant; the approximately 45-kDa protein may represent CREB. These results indicate that CREB/ATF-1-related factors act coordinately with the cell-specific factor GHF1 to mediate cAMP-dependent regulation of hGH-1 gene transcription in anterior pituitary somatotrophs.
...
PMID:Two CGTCA motifs and a GHF1/Pit1 binding site mediate cAMP-dependent protein kinase A regulation of human growth hormone gene expression in rat anterior pituitary GC cells. 829 29

The mechanisms responsible for the diminished lipolytic response of adipocytes to catecholamines after litter removal from lactating rats and their modulation by growth hormone have been investigated. Lactation, litter removal and growth-hormone treatment did not alter the ability of noradrenaline to activate protein kinase A (A-kinase), showing that the defect in signal transduction in rats after litter removal is after A-kinase. Litter removal had no effect on hormone-sensitive lipase activity itself, but the proportion of the lipase associated with the fat droplet was decreased; growth-hormone treatment increased hormone-sensitive lipase activity and the proportion associated with the fat droplet. In addition, a number of other adaptations in the beta-adrenergic signal-transduction system occur during the lactation cycle and in response to growth hormone treatment, including changes in receptor number, adenylate cyclase activity and cyclic AMP phosphodiesterase activity, but a defect in the ability of hormone-sensitive lipase to associate with the lipid droplet appears to be the major reason for the diminished response to catecholamines on litter removal.
...
PMID:Mechanisms involved in the adaptations of the adipocyte adrenergic signal-transduction system and their modulation by growth hormone during the lactation cycle in the rat. 838 54

GHF-1 is a member of the POU family of homeodomain proteins. It is a cell-type-specific transcription factor responsible for determination and expansion of growth hormone (GH)- and prolactin-expressing cells in the anterior pituitary. It was previously suggested that cyclic AMP (cAMP)-responsive protein kinase A (PKA) phosphorylates GHF-1 at a site within the N-terminal arm of its homeodomain, thereby inhibiting its binding to the GH promoter. These results, however, are inconsistent with the physiological stimulation of GH production by the cAMP pathway. As reported here, cAMP agonists and PKA do not inhibit GHF-1 activity in living cells and although they stimulate the phosphorylation of GHF-1, the inhibitory phosphoacceptor site within the homeodomain is not affected. Instead, this site, Thr-220, is subject to M-phase-specific phosphorylation. As a result, GHF-1 DNA binding activity is transiently inhibited during the M phase. This activity is regained once cells enter G1, a phase during which GHF-1 phosphorylation is minimal. Thr-220 of GHF-1 is the homolog of the mitotic phosphoacceptor site responsible for the M-phase-specific inhibition of Oct-1 DNA binding Ser-382. As this site is conserved in all POU proteins, it appears that all members of this group are similarly regulated. A specific kinase activity distinct in its substrate specificity and susceptibility to inhibitors from the Cdc2 mitotic kinase or PKA was identified in extracts of mitotic cells. This novel activity could be involved in regulating the DNA binding activity of all POU proteins in a cell cycle-dependent manner.
...
PMID:M-phase-specific phosphorylation of the POU transcription factor GHF-1 by a cell cycle-regulated protein kinase inhibits DNA binding. 852 34

Protein-tyrosine kinases (PTKs) of the JAK family have been characterized on the basis of their ability to mediate the rapid induction of transcription of interferon-responsive genes through the stimulation of a class of latent cytoplasmic transcription factors known as signal transducers and activators of transcription (STATs). STAT activation, which has been described as being Ras-independent, requires tyrosine phosphorylation, but STAT transactivating activity is enhanced by phosphorylation on serine as well, probably by extracellular signal-regulated kinase/mitogen-activated protein kinase(s) (ERK/MAPK). STATs can be activated upon binding of ligands to receptor PTKs, to G-protein-linked receptors, and to cytokine receptors. Whether JAKs are required for the activation of signaling pathways other than that leading to STAT activation is not known. The binding of growth hormone (GH) to its receptor (GHR) activates JAK2 and STATs as well as ERK/MAP kinases. We have used a transient transfection system in 293 cells to evaluate the requirement for JAK2 in the activation of ERK2/MAPK by GH. We found that JAK2 is required for GH-simulated activation of ERK2/MAPK. Employing the transient expression of dominant negative forms of H-Ras and Raf-1, we determined that the GHR/JAK2-mediated activation of ERK2/MAPK is dependent on both Ras and Raf. Thus, JAK protein-tyrosine kinases may represent a common component in the activation of the ERK2/MAPK and STAT signaling pathways, which appear to bifurcate upstream of Ras activation but converge with ERK/MAPK phosphorylation of STATs.
...
PMID:JAK2, Ras, and Raf are required for activation of extracellular signal-regulated kinase/mitogen-activated protein kinase by growth hormone. 853 33

Growth hormone-releasing hormone (GHRH)-stimulated growth hormone (GH) release from the sheep pituitary is mediated through Ca(2+)-and cyclic AMP-dependent mechanisms. The initial Ca2+ influx is suggested to result from depolarization, whereas a secondary Ca2+ influx is thought to result from second messengers. This study sought to determine whether there was an interaction between these two signal transduction pathways. Sheep pituitary cells were placed in culture for 4 d and were then washed and incubated for 1 hr in serum-free medium before the application of specific antagonises and/or agonists. Both KCl and forskolin stimulated GH release (P < 0.05), but neither produced an effect similar to that of GHRH. The combination of both stimuli, however, mimicked GH release, as seen with a maximal dose of GHRH. Pretreatment with H89 (protein kinase A [PKA] inhibitor) inhibited GHRH, forskolin- and KCl-stimulated GH release (P < 0.001) but had no effect on phorbol myristate acetate (PMA)-stimulated GH release. Verapamil (voltage-dependent Ca2+ channel blocker) inhibited the GHRH effects on GH release (P < 0.0002) but did not influence forskolin or PMA actions. These data suggest that Ca(2+)-dependent pathways converge with cyclic AMP-dependent pathways before or with the activation of PKA. The data also suggest that PKA activation by cyclic AMP alone is insufficient to reproduce either the effects of GHRH stimulation or the combined effects of Ca2+ influx plus PKA activation on GH release. A calmodulin blocker, W7, reduced GHRH-stimulated GH release, a reduction equivalent to the Ca2+ effect on GH release. This suggests that Ca2+ activates calmodulin, which in turn enhances adenylyl cyclase and/or PKA activity to release GH from the sheep pituitary.
...
PMID:Interaction of cyclic AMP- and calcium-dependent mechanisms in the regulation of growth hormone-releasing hormone-stimulated growth hormone release from ovine pituitary cells. 873 64

It is known that withdrawal of somatostatin (SRIF) augments the growth hormone (GH) releasing hormone (GRF)-induced GH secretion. To investigate the mechanism of this augmentation in GH secretion, effects of GRF and SRIF on L-type Ca2+ current (Ba2+ was used as a charge carrier) or primary cultured rat somatotroph were studied by perforated patch clamp technique. The reason is that GRF-induced GH secretion is thought to be causally related to the influx of Ca2+ through L-type Ca2+ channels. 10 mM GRF augmented maximum amplitude of L-type Ba2+ current by 12.2% (n = 12). Subsequent application of SRIF slightly suppressed the currents but the suppression never exceeded the control level of the current. Removal of SRIF, however, promptly augmented the L-type Ba2+ current by 26.8%. Such off-response of SRIF was not observed in cells treated overnight with 100 ng/ml pertussis toxin. Further, specific inhibitor of protein kinase A, H-89 at 1 microM reversibly suppressed the augmentation of L-type Ba2+ current to control level. At 10 microM, H-89 suppressed L-type Ba2+ current by more than 40% from control level. These results suggest that (1) L-type Ca2+ channel of somatotroph is probably phosphorylated in a basal condition and may be slightly modulated by GRF through increased level of cAMP; (2) SRIF only slightly suppress the channel activity; (3) Withdrawal of SRIF facilitates the activity of L-type Ca2+ channel via PTX-sensitive G-protein, although the precise mechanism of this facilitation is unknown. The augmentation by SRIF-pretreatment of GRF-induced GH secretion may be at least partly due to the facilitation of the activity of L-type Ca2+ channel.
...
PMID:Withdrawal of somatostatin augments L-type Ca2+ current in primary cultured rat somatotrophs. 874 22

Electrophysiological responses induced by human (h) growth hormone-releasing hormone (GHRH) were analyzed using the perforated whole cell clamp technique in human growth hormone (GH)-secreting adenoma cells. Application of hGHRH depolarized the membrane by increasing Na+ conductance. The reversal potential of the hGHRH-induced current was -20 to 0 mV. The channel was permeable to Na+, Li+ and K+ but not to TMA+. These properties were compatible with those of nonselective cation channels. Similar nonselective cation current was activated by 8-bromoadenosine 3',5'-cyclic monophosphate and forskolin, and the activation of the hGHRH-induced current was inhibited by protein kinase A (PKA) inhibitors, (R)-p-adenosine 3',5'-cyclic monophosphate and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoleinsulfonamide, and PKA inhibitor peptide PKI-(5-24), indicating that hGHRH-induced current was activated by PKA. Cholera toxin pretreatment eliminated the hGHRH-induced current, suggesting that Gs is involved in the activation of this current. This current became irreversible when the cells were pretreated with okadaic acid, suggesting that the recovery of the hGHRH-induced current was mediated by a serine/threonine protein phosphatase. GHRH-induced GH secretion was inhibited in Na+-free medium, suggesting the importance of the nonselective cation current on hGHRH-induced GH secretion. In human GH-secreting nonadenoma cells, hGHRH increased Na+ conductance, as was the case in GH-secreting adenoma cells.
...
PMID:GHRH activates a nonselective cation current in human GH-secreting adenoma cells. 876 91

Hypothalamic growth hormone-releasing hormone (GHRH) stimulates growth hormone (GH) production and somatotroph proliferation by binding to a seven transmembrane-domain receptor, linked to Gs. Gs stimulates production of cyclic adenosine 3'-5'-monophosphate (cAMP) and hence activation of protein kinase A (PKA). A subgroup of pituitary somatotroph adenomas has been demonstrated, which has constitutive activation of Gs, with reduced in vitro responsiveness to agents that stimulate Gs. Subsequently, somatotroph adenomas have been identified, which have activating mutations of Gs (gsp). However, there are no clear clinical or biochemical phenotypic characteristics that enable gsp-positive and gsp-negative tumors to be differentiated from one another. Gsp mutations occur in 35% to 40% of somatotroph adenomas in caucasians, but have a much lower reported prevalence of 4% to 9% in the Japanese population. G-protein mutations also occur in clinically nonfunctioning pituitary tumors and, rarely, in corticotroph adenomas. There is little direct evidence at present to suggest that the gsp mutation has a primary oncogenic role in the pathogenesis and function of pituitary tumors. Further functional studies are needed. The gsp mutation is probably one of several oncogenic mutations required for pituitary tumor development.
...
PMID:Gs protein mutations and the pathogenesis and function of pituitary tumors. 876 4

The effect of human growth hormone-releasing hormone (hGHRH), a potent stimulator of adenylate cyclase in somatotrophs on the voltage-gated sodium current was determined by perforated patch clamp of cultured rat somatotrophs The amplitude of the voltage-gated sodium current was augmented by 65.3 +/- 20.6% (mean +/- SE, n = 7) by 10 nM hGHRH. This augmentation was reversibly blocked by 10 microM H-89 a specific inhibitor for adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. The membrane-permeant analogue of cAMP, dibutyryl cAMP (5 mM), also augmented the voltage-gated sodium current by 39.6 +/- 7.4% (n = 10). There were no effects of hGHRH or dibutyryl cAMP on steady-state inactivation of the sodium current. In contrast, in the whole cell configuration of patch clamp, no augmentation of the sodium current was observed by hGHRH or by the membrane-permeant analogue of cAMP. These results suggest that hGHRH augments the peak amplitude of the voltage-gated sodium current in rat somatotrophs via phosphorylation by cAMP-dependent protein kinase. For this augmentation, the intracellular environment must be kept relatively intact.
...
PMID:Growth hormone-releasing hormone augments voltage-gated Na+ current in cultured rat pituitary cells. 877 37

To investigate whether expression of the renal angiotensinogen gene is regulated by dopaminergic receptors, we used opossum kidney (OK 27) cells with a fusion gene containing the 5'- flanking regulatory sequence of the rat angiotensinogen gene fused with a human growth hormone (hGH) gene as a reporter [pOGH, angiotensinogen nucleotide (N) -1498/+18], permanently integrated into their genomes. The level of expression of pOGH (angiotensinogen N-1498/+18) in OK 27 was evaluated by the amount of immunoreactive hGH (ir-hGH) secreted into the culture medium. In the absence of 3-isobutyl-1-methylxanthine (IBMX), addition of dopamine (10(-13) to 10(-5)M) had minimal effect on the expression of the pOGH (angiotensinogen N-1498/+18) in OK 27 cells. In the presence of IBMX, addition of low concentrations (10(-13) and 10(-7) M) of dopamine stimulated the expression of pOGH angiotensinogen N-1498/+18) in OK 27 cells in a dose-dependent manner, whereas high concentrations (i.e., > 10(-7) M) had minimal effect. The stimulatory effect of dopamine on the expression of pOGH (angiotensinogen N-1498/+18) was inhibited by the presence of SCH-23390 (D1-dopaminergic receptor antagonist) and spiperone (D2-dopaminergic receptor antagonist), but not by ketanserin (5 HT2/5HT1c-serotonergic receptor antagonist). Moreover, the stimulatory effect of dopamine was inhibited by the presence of U-73122 (an inhibitor of phospholipase C and phospholipase A2) or staurosporine (an inhibitor of protein kinase C) or (R)-p-adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMP[S]; an inhibitor of cAMP-dependent protein kinase AI and II). Addition of low concentrations (10(-13) to 10(-9)M) of SKF-82958 (D1-dopaminergic receptor agonist) or PPHT (D2-dopaminergic receptor agonist) also stimulated the expression of pOGH (angiotensinogen N-1498/+18). The stimulatory effect of SKF-82958 was inhibited by the presence of SCH-23390 or Rp-cAMP[S], whereas the effect of PPHT was inhibited by the presence of spiperone or staurosporine. These studies demonstrate that the expression of pOGH (angiotensinogen N-1498/+18) in OK 27 cells is modulated by dopaminergic receptor agonists.
...
PMID:Dopaminergic receptors and angiotensinogen gene expression in opossum kidney cells. 885 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---