Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenylate cyclase activity of rabbit bone marrow erythroblasts decreased continuously as the cells developed. The proerythroblasts were the richest cells in cAMP. No changes in cAMP levels were observed after the final cell division. cAMP-phosphodiesterase activity declined rapidly during the early period of erythroid cell development and remained constant but extremely low after condensation of the nucleus. Both cytosolic cAMP-binding capacity and cAMP-dependent protein kinase activity decreased in dividing erythroblasts when calculated in terms of cell number but remained constant per cell volume. Membrane-associated protein kinase was found to be cAMP-dependent only in the dividing cells. The adenylate cyclase activity of both early and late erythroblasts was stimulated by GTP and p (NH)ppG, whereas the stimulating effect of the beta-adrenergic drug L-isoprenaline was limited to the immature dividing cells. The lack of response of non-dividing erythroblasts to beta-adrenergic stimuli is not due to loss of beta-receptors, since both dividing and non-dividing cells bind 125I-iodohydroxybenzylpindolol with equal affinities. The number of beta-adrenergic receptors per cell was 2-fold higher in the dividing cells. No significant change in binding affinity for GTP and p (NH) ppG during erythroblast development was observed.
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PMID:Characteristics of the adenylate cyclase system of differentiating rabbit bone marrow erythroblasts. 632 69

Avian erythroblastosis virus (AEV) is an oncogenic retrovirus capable of transforming both fibroblasts and immature erythroid cells. The v-erb-B locus within the AEV genome encodes a glycosylated protein, expression of which is required for oncogenic transformation of either cell type. Subcellular localization of the v-erb-B glycoprotein in AEV-transformed cells is reported here. Results indicate that the v-erb-B protein is synthesized on dense membrane fractions and appears to possess the properties of an integral membrane protein. The bulk of the v-erb-B protein remains with dense membranes after synthesis, although a small quantity may slowly become associated with the plasma membrane. The biogenesis and subcellular location of the v-erb-B protein are thus quite different from those of the transforming proteins that display protein kinase activity. These differences are especially provocative because the amino acid sequences of the v-erb-B protein and the protein kinases are closely related to one another.
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PMID:Subcellular localization of the v-erb-B protein, the product of a transforming gene of avian erythroblastosis virus. 633 Sep 78

A model has been presented for the role of the kidney in the physiologic and pathophysiologic control of erythropoiesis. It is postulated that an oxygen deficit created by anemia or hypobaric hypoxia results in the release of prostacyclin and its metabolite 6-keto PGE1, and the release of PGE2 with ischemic hypoxia. Prostacyclin, 6-keto-PGE1, or PGE2 activation of adenylate cyclase, an increase in cyclic AMP, activation of a protein kinase and the phosphorylation of hydrolases, which have been released from lysosomes by hypoxia, lead to increased biosynthesis of erythropoietin (Ep). The mechanism of labilization of lysosomes and the release of hydrolases from these cell organelles is postulated to be related to increases in cyclic GMP levels in a renal cell. An Ep-producing human renal carcinoma cell line grown in tissue culture has been demonstrated to produce significant amounts of PGE2. Meclofenamate, an inhibitor of prostaglandins synthesis, was found to inhibit in vitro production of PGE2, Ep, and dome formation in these renal carcinoma cells, giving support to our hypothesis that pathophysiologic production of Ep tumor cells depends upon prostaglandins production. An Ep-producing clone from this renal carcinoma cell line has been developed that contains low electron density (LED) cells after the cells reach confluency, which show a cytoplasm, with abundant and widely dilated endoplasmic reticulum, an oval nucleus, dispersed chromatin, and prominent nucleoli. These are the cells responsible for dome formation and Ep production. Non-EP-producing clones have also been produced from this renal carcinoma cell line, which did not produce domes even at high cell density and had a distinctly different cell type than the Ep-producing clone. Thus, it is postulated that prostacyclin (PGI2) and its metabolite 6-keto PGE1 play a significant role in hypoxic hypoxia stimulation of Ep production and PGE2 is involved in ischemic hypoxia and renal carcinoma cell production of Ep. A modulating effect of PGE2 and PGD2, the two primary bone marrow prostaglandins, has been proposed in Ep stimulation of the erythroid progenitor cell compartment (CFU-E and BFU-E).
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PMID:Effects of prostaglandins on erythropoiesis. 654 52

The hemoglobin regulator, 2,3-bisphosphoglycerate (glycerate-2,3-P2) has been shown to modulate the activity of casein kinase II from rabbit reticulocytes. Kinetic results were obtained with the exogenous substrate, beta-casein and the endogenous substrates, initiation factors (eIF-) 2 and 3. Experiments carried out to determine the interaction between glycerate-2,3-P2, Mg2+, substrate, and casein kinase II led to the following conclusions: 1) glycerate-2,3-P2 inhibition was competitive with respect to the protein substrate and noncompetitive with respect to ATP; 2) inhibition was not caused by depletion of ATP-Mg2+ as a consequence of Mg2+ complexation with glycerate-2,3-P2; 3) the response curve for glycerate-2,3-P2 was cooperative, but the cooperativity decreased as salt concentration increased; 4) glycerate-2,3-P2 inhibition was dependent on Mg2+ concentration up to about 5 mM MgCl2 but did not parallel glycerate-2,3-P2 X Mg2+ complex formation indicating that the Mg2+ dependence was not due to the formation of a glycerate-2,3-P2 X Mg2+ complex; 5) experiments with analogs of glycerate-2,3-P2 showed that the binary phosphate grouping was important in determining inhibition by glycerate-2,3-P2 while the presence of the carboxylate-phosphate pair was much less important; 6) low levels of glycerate-2,3-P2 stimulated phosphorylation of beta-casein, eIF-2, and eIF-3; the extent of stimulation was dependent on the affinity for casein kinase II and the level of the substrate. These effects were observed in the range of glycerate-2,3-P2 concentrations predicted for intracellular fluctuations in this metabolite. Therefore, it was concluded that glycerate-2,3-P2 could function both as an activator and an inhibitor of casein kinase II in the erythroid cell by binding at the substrate binding site.
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PMID:Regulation of casein kinase II by 2,3-bisphosphoglycerate in erythroid cells. 658 3

Erythropoietin is a cytokine which specifically regulates differentiation and proliferation of erythroid progenitor cells. We show here that binding of erythropoietin to its receptor induced activation of protein tyrosine kinases including Jak2, and of Ras, Raf-1, mitogen-activated protein (MAP) kinase kinase and MAP kinases (ERK1 and ERK2). Taken together with other observations, erythropoietin receptor-mediated signal activates MAP kinase cascade, which is the common signaling pathway activated by other cytokines and growth factor receptors with tyrosine kinase activity.
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PMID:Activation of mitogen-activated protein kinase cascade through erythropoietin receptor. 752 95

We have reported that erythropoietin induces a dose-dependent increase in cytosolic calcium ([Cai]) in single human peripheral blood BFU-E derived erythroblasts which is specific for stage of differentiation and that this increase is modulated by erythropoietin through an ion channel permeable to Ca2+. Here, the role of protein phosphorylation in the increase in intracellular free calcium [Cai] stimulated by erythropoietin was studied with digital video imaging. Preincubation of day 10 erythroblasts with a broad inhibitor of serine/threonine and tyrosine kinases, staurosporine (100 nM), blocked the increase in [Cai] over 20 min following erythropoietin stimulation. However, erythropoietin-induced calcium influx was unaffected by preincubation of cells with specific inhibitions of protein kinase C (calphostin C) or the cAMP- or cGMP-dependent kinases (KT 5720, HA 1004), and [Cai] did not increase following stimulation with phorbol 12-myristate 13-acetate (PMA) or dibutyryl cAMP. These results suggest that neither protein kinase C nor protein kinase A mediate the erythropoietin-induced [Cai] increase. In contrast, preincubation with genistein, a tyrosine kinase inhibitor, blocked the erythropoietin induced increase in [Cai]. To further study calcium entry in erythroblasts, we determined mastoparan, a peptide from wasp venom, induced a dose-dependent rise in [Cai] in erythroblasts which required external calcium. Stimulation of erythroid precursors with 10 microM mastoparan resulted in an increase in [Cai] from 52 +/- 3 nM to 214 +/- 36 nM which peaked at 20 min. The mastoparan-induced [Cai] increase was also dependent on tyrosine phosphorylation since it was blocked by preincubation with genistein. These results demonstrate that both erythropoietin and mastoparan stimulate calcium entry by a mechanism which has a genistein sensitive step and suggest that tyrosine kinase activation is required for the rise in [Cai] to occur.
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PMID:Erythropoietin modulation of intracellular calcium: a role for tyrosine phosphorylation. 753 33

An established megakaryoblastic cell line, MEG-01s, was used to study receptor expression and receptor-mediated responses to factors known to affect megakaryocytopoiesis. In addition, the antigenic characteristics of this cell line were further defined. MEG-01s cells were CD34+CD33+CD38 +/- HLA-DR- and expressed erythroid and granulocytic differentiation antigens as well as many megakaryocytic lineage-restricted antigens. These cells also expressed receptors for interleukin-3 (IL-3), IL-6, and stem cell factor (SCF), as measured by flow cytometry and/or RNA expression. MEG-01s cell proliferation or survival was only marginally influenced by these factors and their combinations. c-kit, the receptor for SCF, was downmodulated by its ligand. This modulation was time-dependent, appeared to involve receptor conformational changes, and became concentration-dependent by day 3. Northern blot analysis indicated that amounts of c-kit RNA increased as downmodulation proceeded. IL-3 induced IL-6 secretion in these cells, which was augmented by a protein kinase-C (PKC) inhibitor, H7, and reduced by a tyrosine kinase inhibitor, genistein. Evidence for autocrine regulation of this cell line by IL-6 was demonstrated by the inhibitory effects of an antisense oligonucleotide on 3H-thymidine (3H-TdR) incorporation. These cells should prove useful for studies of the early signal transduction mechanisms involved in cytokine function.
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PMID:MEG-01s cells have receptors for and respond to IL-3, IL-6, and SCF. 753 84

When murine erythroleukemia (MEL) cells are induced to differentiate by hexamethylene bisacetamide (HMBA), erythroid-specific genes are transcriptionally activated; however, transcriptional activation of these genes is severely impaired in cAMP-dependent protein kinase (protein kinase A)-deficient MEL cells. The transcription factor NF-E2, composed of a 45-kDa (p45) and an 18-kDa (p18) subunit, is essential for enhancer activity of the globin locus control regions (LCRs). DNA binding of NF-E2 and alpha-globin LCR enhancer activity was significantly less in HMBA-treated protein kinase A-deficient cells compared to cells containing normal protein kinase A activity; DNA binding of several other transcription factors was the same in both cell types. In parental cells, HMBA treatment and/or prolonged activation of protein kinase A increased the amount of NF-E2.DNA complexes without change in DNA binding affinity; the expression of p45 and p18 was the same under all conditions. p45 and p18 were phosphorylated by protein kinase A in vitro, but the phosphorylation did not affect NF-E2.DNA complexes, suggesting that protein kinase A regulates NF-E2.DNA complex formation indirectly, e.g. by altering expression of a regulatory factor(s). Thus, protein kinase A appears to be necessary for increased NF-E2.DNA complex formation during differentiation of MEL cells and may influence erythroid-specific gene expression through this mechanism.
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PMID:cAMP-dependent protein kinase is necessary for increased NF-E2.DNA complex formation during erythroleukemia cell differentiation. 772 32

Reticulocytes contain an eukaryotic initiation factor-2 alpha (eIF-2 alpha) kinase that is negatively regulated by hemin. This protein kinase, which has been termed heme-regulated inhibitor and heme-controlled repressor (HCR), has a strong inhibitory effect on the initiation of protein synthesis and plays an important role in translational control in these cells. Previous evidence has suggested that HCR may be an erythroid-specific enzyme. As reported herein, we have cloned and characterized the cDNA encoding an eIF-2 alpha kinase from rat brain. The predicted amino acid sequence of the kinase from rat brain shows 82% homology to rabbit reticulocyte HCR with the greatest variation concentrated in a central region of approximately 135 amino acids located between protein kinase subdomains IV and VI. We have expressed the rat brain cDNA in Escherichia coli and have demonstrated that the recombinant enzyme is a hemin-sensitive eIF-2 alpha kinase. We have also shown that mRNA recognized by the rat brain cDNA is expressed in a wide range of non-erythroid rat tissues at a lower but significant level compared with reticulocytes. These findings raise the possibility of additional, uncharacterized roles for HCR in non-erythroid cells.
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PMID:Cloning and characterization of cDNA encoding rat hemin-sensitive initiation factor-2 alpha (eIF-2 alpha) kinase. Evidence for multitissue expression. 790 90

Two interferon (IFN) alpha-regulated genes, IRF1/ISGF2 and PKR/p68 kinase, may function as tumor suppressor genes suggesting that the IFN system may function as a tumor suppressor system. We report that the expression of the alpha subunit of the type I IFN receptor in human K-562 cells had anti-oncogenic effects that include a marked decrease in: (i) cell proliferation rate, (ii) the cell density at which growth arrest normally occurs, and (iii) the tumorigenicity in nude mice. Furthermore, expression of the alpha subunit in K-562 cells induced erythroid differentiation. While most cytokine receptors become activated after binding their corresponding ligands, the overexpression of the alpha subunit has a physiological effect in the absence of its natural ligand, type I IFNs, suggesting a novel function for this type I IFN receptor subunit. The anti-oncogenic effect of the alpha subunit is mediated by a pathway that does not involve two tumor suppressor genes induced by type I IFNs, the transcriptional regulator IFN response factor-1 and the RNA-dependent protein kinase, or the p135tyk2 tyrosine kinase that directly associates and phosphorylates the alpha subunit.
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PMID:Ligand-independent anti-oncogenic activity of the alpha subunit of the type I interferon receptor. 796 37


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