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

In vertebrates, unfertilized eggs are arrested at second meiotic metaphase by a cytostatic factor (CSF), an essential component of which is the product of the c-mos proto-oncogene. CSF prevents ubiquitin-dependent degradation of mitotic cyclins and thus inactivation or the M phase-promoting factor (MPF). Fertilization or parthenogenetic activation triggers a transient increase in the cytoplasmic free Ca2+ (reviewed in refs 5 and 6), inactivates both CSF and MPF, and releases eggs from meiotic metaphase arrest. A calmodulin-dependent process is required for cyclin degradation to occur in cell-free extracts prepared from metaphase II-arrested eggs (CSF extracts) when the free Ca2+ concentration is transiently raised in the physiological micromolar range. Here we show that when a constitutively active mutant of calmodulin-dependent protein kinase II (CaM KII) is added to a CSF extract, cyclin degradation and Cdc2 kinase inactivation occur even in the absence of Ca2+, and the extract loses its ability to cause metaphase arrest when transferred into embryos. Furthermore, specific inhibitors of CaM KII prevent cyclin degradation after calcium addition. Finally, the direct microinjection of constitutively active CaM KII into unfertilized eggs inactivates Cdc2 kinase and CSF, even in the absence of a Ca2+ transient. The target for Ca(2+)-calmodulin is thus CaM KII.
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PMID:Calmodulin-dependent protein kinase II mediates inactivation of MPF and CSF upon fertilization of Xenopus eggs. 823 78

The Raf-1 proto-oncogene product is a highly regulated serine/threonine kinase that functions in signal transduction downstream from growth factor receptors and upstream from nuclear proto-oncogene products. Using a transient cotransfection assay we have found that activated Raf-1 activates expression from the HIV-LTR. Analysis of a series of 5' deletion and point mutations revealed the NF-kappa B motifs as the Raf-responsive element in the HIV-LTR. Moreover, Raf-BXB activated expression from heterologous promoters driven by the HIV NF-kappa B binding sites. In addition to Raf, we show that v-Src, v-H-Ras and v-Mos activate HIV-LTR expression through the NF-kappa B binding sites and v-H-Ras-induced HIV-LTR expression is mediated by Raf-1. These findings may have implications for the involvement of the cellular homologues of these oncogenes in the switch from latent to productive infection by HIV in response to T-cell activation.
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PMID:Oncogene activation of HIV-LTR-driven expression via the NF-kappa B binding sites. 825 80

The product of the c-raf-1 proto-oncogene, Raf-1, is known to encode a 74-kDa ubiquitously expressed cytoplasmic serine/threonine kinase. Various growth factors such as epidermal growth factor, acidic fibroblast growth factor, platelet-derived growth factor, insulin, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-2, IL-3 and erythropoietin have been shown to induce phosphorylation of Raf-1, thereby activating Raf-1 kinase. Raf-1 is, thus, believed to play a role in coupling growth factor receptors to proliferation. We have examined the role of Raf-1 in the mitogenic response of human peripheral blood-derived IL-2 receptor expressing T cells to human recombinant IL-2 employing c-raf antisense (AS) oligodeoxyribonucleotide. Uptake studies of oligonucleotides indicated that incorporation of oligomers was maximal at 4 h and oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of T cells with the AS oligodeoxyribonucleotide in intracellular duplex formation followed by efficient translation blockade of c-raf-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and did not interfere with translation of c-raf-1, suggesting specific elimination of c-raf-1 by the AS oligomer. Proliferation of T cells ([3H]thymidine incorporation) following exposure to IL-2 was substantially reduced when the c-raf-1 AS oligodeoxyribonucleotide was added to cultures, while the mitogenic response to this factor remained almost unaffected in the presence of S and NS oligodeoxyribonucleotides.
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PMID:The mitogenic response of T cells to interleukin-2 requires Raf-1. 825 28

The proto-oncogene c-fos is important in cell growth, differentiation and development. Several promoter elements have been identified as mediators for the induction of c-fos by serum, tumor promoting agents, epidermal growth factor and other stimuli. Stressors, including heat shock, arsenite and cadmium can induce c-fos transcription, but a heat shock element in the c-fos promoter has not been described. In this report we show that the induction of c-fos by heat shock, arsenite and cadmium can be mediated by the serum response element. Furthermore we show that casein kinase II, which has been proposed to be involved in serum induction via the serum response element, may also be involved in heat shock, arsenite and cadmium induction of c-fos.
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PMID:c-fos induction by stress can be mediated by the SRE. 826 88

Nucleotide sequencing of the SalI j region of the virulent Malawi (LIL20/1) strain of African swine fever virus (ASFV) identified an open reading frame (ORF), designated j9L, with extensive similarity to the family of protein kinases. This ORF encodes a 35.1-kDa protein of 299 amino acids which shares 24.6% amino acid identity with the human pim-1 proto-oncogene and 21.0% identity with the vaccinia virus B1R-encoded protein kinase. The ASFV ORF contains the motifs characteristic of serine-threonine protein kinases, with the exception of the presumed ATP-binding site, which is poorly conserved. The ORF was expressed to high levels in Escherichia coli, and the recombinant enzyme phosphorylated a calf thymus histone protein on serine residues in vitro. An antibody raised to an amino-terminal peptide of the ASFV protein kinase was reactive with the recombinant protein in Western immunoblot analyses and was used to demonstrate the presence of the protein kinase in ASF virions.
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PMID:African swine fever virus encodes a serine protein kinase which is packaged into virions. 833 22

The product of the c-myb proto-oncogene is a highly conserved transcription factor that has been shown to function as both a transactivator and repressor. The v-myb oncogenes of E26 leukemia virus and avian myeloblastosis virus (AMV) encode proteins truncated at both the amino and carboxy termini, deleting portions of the DNA-binding and negative regulatory domains present in c-Myb. Similar truncations of c-Myb alter its function, suggesting that the viral proteins lack important regulatory sequences. Interestingly, eight potential sites of phosphorylation by proline-directed protein kinases conserved between the avian, murine and human Myb proteins are clustered in or near the negative regulatory domain of c-Myb. The majority of these sites are deleted in both the E26 and AMV viral proteins. In this paper we show that one proline-directed protein kinase, p42mapk, phosphorylates bacterially synthesized avian and murine c-Myb but not AMV v-Myb in vitro. We find that p42mapk phosphorylates c-Myb on serine and threonine, but not on tyrosine. Furthermore, deletion analysis indicates that the sites of phosphorylation map to the C-terminal negative regulatory domain. We speculate that the inability of v-Myb to be phosphorylated by p42mapk may contribute to its oncogenic properties.
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PMID:c-Myb and v-Myb are differentially phosphorylated by p42mapk in vitro. 833 48

The proto-oncogene Raf-1 is a cytoplasmic serine/threonine kinase implicated in the signaling process in cell proliferation. To determine if Raf-1 is sufficient and necessary to transmit mitogenic signals to growth-responsive genes, we examined the effect of constitutively activated (v-raf) or inhibitory (Raf-C4) Raf-1 proteins on reporter gene activation in transient expression assays of NIH 3T3 cells. In serum-starved cells, v-raf strongly activated transcription from the promoters of the immediate-early genes c-fos and egr-2, as well as the proximal or B promoter of the late growth response gene rep-3 (rep-3b). Two other late response gene promoters, cad and dhfr, were only modestly activated by v-raf, however. An individual serum response element from the c-fos or egr-2 promoter conferred both serum-inducibility and v-raf-responsiveness to a heterologous promoter. Consistent with the degree to which antisense c-raf-1 RNA and dominant-negative Raf-1 proteins interfere with NIH 3T3 cell proliferation, Raf-C4 reduced serum-induced transcription from the egr-2 and rep-3b promoters in a dose-dependent manner by 50%. In contrast, Raf-C4 did not significantly reduce transcription from the c-fos or cad promoters or the serum response element-driven heterologous promoters. We conclude that Raf-1 is both sufficient and necessary to activate a subset of early and late growth response genes.
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PMID:An inhibitory Raf-1 mutant suppresses expression of a subset of v-raf-activated genes. 834 Mar 92

The hepatocarcinogenicity of peroxisome proliferators (PPs) in rodents has been attributed both to oxidative DNA damage resulting from excessive leakage of peroxisomal H2O2 and to increased hepatocellular replication that may be independent of peroxisome proliferation. Because of the growing association between tumor promotion and alterations in growth-regulatory signal transduction pathways, we investigated whether PPs can modulate these pathways in a mouse liver epithelial cell line, BNL-CL.2. We tested two PPs that differ markedly in rodent tumorigenicity for their ability to activate immediate-early proto-oncogene expression. 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy-14643), a highly tumorigenic PP, was an exceptionally strong inducer of c-fos expression. Wy-14643 was also stronger than DEHP in stimulating c-jun expression, whereas both PPs were fairly strong inducers of jun-B and jun-D. The induction of fos and jun expression by Wy-14643 was specifically inhibited by the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H-7). DEHP-induced gene expression was strongly inhibited by H-7, but was also partially inhibited by an inhibitor of protein kinase A. The activation of fos and jun gene expression by PPs was independent of peroxisome proliferation since it was an immediately-early response not requiring protein synthesis and since the cell lines used in this study do not undergo peroxisome proliferation. Our r results raise the possibility that the carcinogenicity of PPs may be due, in part, to epigenetic modulation of growth-regulatory signal transduction pathways.
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PMID:Activation of immediate-early gene expression by peroxisome proliferators in vitro. 835 87

The c-raf-1 proto-oncogene is the cellular homologue of v-raf, the oncogene of the acutely transforming retrovirus 3611-MSV. The product of c-raf-1 (raf-1) is a 74-kDa cytoplasmic serine/threonine protein kinase. We previously reported that antisense human c-raf-1 cDNA transfection results in reduction of the endogenous c-raf-1 transcript, decreased tumor growth rate, and enhanced radiation sensitivity of SQ-20B tumor cells established from a radiation-resistant laryngeal squamous cell carcinoma. In the study reported here, we used cDNA-linked polymerase chain reaction amplification and nucleotide sequencing to examine the structure of the 3233-bp SQ-20B c-raf-1 cDNA. The 812-bp c-raf-1 promoter region was analyzed by genomic DNA amplification followed by cloning and sequencing. Sequence comparison with a previously published c-raf-1 sequence indicated no structural changes within the coding region of SQ-20B c-raf-1. However, a 4-bp deletion was observed in the 3' untranslated region within exon 17. This deletion was also present in a c-raf-1 cDNA clone isolated from a SQ-20B cDNA library. While the possibility of a 3' transcriptional control mechanism cannot be ruled out, it appears that the raf-1 protein kinase may regulate the development of radioresistant malignancies via interaction with other molecules in the damage and repair-related signal transduction pathways.
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PMID:Nucleotide sequence analysis of c-raf-1 cDNA and promoter from a radiation-resistant human squamous carcinoma cell line: deletion within exon 17. 835 93

In eucaryotes, M-phase promoting factor (MPF) triggers meiosis in germ cells and mitosis in somatic cells. MPF is composed of two proteins of which one is homologous with the protein kinase encoded by gene cdc2 of Schizosaccharomyces pombe (p34cdc2) and the other is a cyclin whose concentration oscillates during the cell cycle. Inactivation of p34cdc2 (MPF) requires cyclin degradation, which occurs during the metaphase-anaphase transition of the M-phase. Cyclin degradation is not only associated with cell cycle progression, but is also required for this event. At the G2/M transition, p34cdc2 protein kinase is activated and catalyzes phosphorylation of numerous key proteins, thus enabling cell changes to occur. p34cdc2 undergoes multiple-site phosphorylation in a cell cycle-dependent manner. At onset of mitosis, the protein phosphatase cdc25 catalyzes dephosphorylation of the p34cdc2 kinase at the threonine 14 and tyrosine 15 sites. This event may be the rate-limiting step controlling onset of mitosis in cells of vertebrates. A second protein kinase, encoded by the proto-oncogene c-mos, acts as a cytostatic factor preventing cyclin degradation and keeping unfertilized eggs from progressing beyond the second meiotic metaphase.
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PMID:[Control of cell division in eucaryotes]. 839 83


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