Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypothetical Products from Noncoding Frames (i.e., HyPNoFs) are hypothetical, not-coded proteins, translated from alternate reading frames (i.e., coding + 1 and coding + 2) of cDNAs. HyPNoFs of CD4, PKC, oncostatin, bcl-2 proto-oncogene, tumor suppressor p53, cystic fibrosis transmembrane regulator (CFTR), and tumor necrosis factors alpha and beta were searched as query sequences vs the SWISS-PROT data bank. Homology searchers carried out revealed that hypothetical products (i.e., HyPNoFs) may share high similarity with real protein products actually coded. Sequence similarity of hypothetical products to real proteins is sometimes very high, suggesting common conformational features, according to the Sander and Schneider cutoff value. This finding supports the hypothesis that eukaryotic DNA, currently considered to be monocistronic, might occasionally have polycistronic regions, carrying different protein messages on overlapping frames. As yet, polycistronic genes have been observed in viral genomes only. The presence of polycistronic regions in eukaryotic genes is likely reminiscent of an ancient strategy, rather than a present feature of the genome in eukaryotes. These data suggest that thorough investigation of HyPNoFs is likely to improve our ability to trace genes' evolution and to investigate structure-function relationships of protein and DNA sequences.
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PMID:Investigating hypothetical products from noncoding frames (HyPNoFs). 754 50

The hypothalamic neuropeptide TRH, which stimulates prolactin (PRL) release and PRL gene transcription, also raises c-fos proto-oncogene mRNA levels in GH3B6 rat pituitary cells. C-fos is assumed to be involved in the transduction of external signals to the nucleus as a component of AP1 transcription factor, a protein complex that contains a member of the jun proto-oncogene family. We have thus looked for the member(s) of the jun family that could be the partner of c-fos in TRH-stimulated GH3B6 cells. The common biphasic pattern of jun B and c-fos mRNA regulation under TRH exposure, i.e., an early peak and a long-lasting plateau phase, suggested that jun B was the best candidate. Then, to better understand the mode of action of TRH and to look for possible functions of c-fos and jun B in these cells, we have investigated the role of different intracellular signalings in the induction of each proto-oncogene. This was done taking as a model that the effects of TRH on PRL release and PRL gene transcription has been previously ascribed to the coupling of the TRH receptor to the activation of both protein kinase C- and calcium-dependent mechanisms. An extensive pharmacological analyses revealed that PKC-, Ca2+ but also protein kinase A-dependent mechanisms are involved in TRH-induced c-fos and jun B mRNA early responses in GH3B6 cells. The overall study also revealed specific features in the control by TRH of each proto-oncogene by some intracellular messengers. Finally, considering the fact that second long lasting phase of proto-oncogene expression was found associated with increased PRL mRNA accumulation whatever the stimulus, it might be proposed that AP1 [c-Fos/Jun B] factor could be involved in the regulation of PRL gene expression. Such hypothesis was furthermore supported by preliminary gel-shift experiments. Nevertheless, in view of the systematic coincidence between acute PRL release and early proto-oncogene induction, a role for c-fos and jun B in the control of genes involved in the secretory process might also be suggested.
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PMID:[Stimulation of C-fos and jun B proto-oncogenes: potential role of TRH effects in clone cell line with prolactin (GH3B6)]. 764 71

The induction of transcription of specific genes after exposure to ionizing radiation has previously been reported after lethal doses of radiation (2-50 Gy). Little attention has been focused on expression of "immediate early genes" after low doses of ionizing radiation, where cell viability remains high. This dose range (0.25-2.0 Gy) is above the diagnostic dose level but at or below the doses typical for a single exposure in fractionated radiotherapy treatment of cancer. In this study, it was observed that doses in the range of 0.25-2.0 Gy induced different amounts of the mRNAs of the proto-oncogenes c-fos, c-jun, c-myc and c-Ha-ras at a given dose and time in Epstein-Barr virus-transformed human lymphoblastoid 244B cells. A maximum response was seen after a dose of 0.5 Gy for all but c-fos, which showed a maximum response after exposure to 0.25 Gy. Time-course studies demonstrated that, for all four proto-oncogenes, the induction was transient, reaching a maximum at 1 h and declining to the constitutive level at 4 h after irradiation. Using second-messenger specific inhibitors, the signaling pathways involved in the induction of these proto-oncogenes was also investigated. The results showed that all four of the proto-oncogenes induced after 0.5 Gy shared a common pathway of tyrosine kinase activation. Other signaling pathways included protein kinase C, reactive oxygen intermediates and calcium-dependent kinases; these were found to be differentially involved in the induction of transcription of the individual proto-oncogenes. In summary, this study suggests that low-dose ionizing radiation (0.25-2.0 Gy) can modulate expression of immediate early genes. Secondly, the activation of immediate early genes after low-dose exposure involves multiple second-messenger signaling pathways. Third, the magnitude of involvement of the different signaling pathways after low-dose radiation is different for each proto-oncogene expressed.
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PMID:Induction of transcription of "immediate early genes" by low-dose ionizing radiation. 765 63

The molecular mechanisms by which overloaded cardiac myocytes increase the cell size (hypertrophy) remain unknown. We have previously shown that mechanical loading increased the protein synthesis and the expression of proto-oncogene c-fos mRNA (Komuro, I., Kaida, T., Shibazaki, Y., Kurabayashi, M., Katoh, Y. Hoh, E., Takaku, F., and Yazaki, Y. (1990) J. Biol. Chem. 265, 3595-3598; Komuro, I., Katoh, Y., Kaida, T., Shibazaki, Y., Kurabayashi, M., Hoh, E., Takaku, F., and Yazaki, Y. (1991) J. Biol. Chem. 266, 1265-1268). It has been known that both mitogen-activated protein (MAP) kinase and S6 kinase can be activated by many kinds of growth factors. To clarify whether MAP kinase(s) and S6 kinase(s) are associated with the intracellular signaling of cardiac hypertrophy induced by mechanical loading, we cultured neonatal rat cardiac myocytes in deformable dishes and imposed an in vitro mechanical loading by stretching the adherent myocytes. In this study, we demonstrated that 1) myocyte stretching maximally activated a kinase activity toward myelin basic protein (MBP) at 10 min after stretching, and the kinase activity returned to the control level at 30 min after stretching; 2) kinase assays in MBP-containing gel, after sodium dodecyl sulfate-polyacrylamide gel electrophoresis, revealed that stretch-induced MBP kinase activity mainly migrated at 42 kDa in the immunoprecipitated fraction of anti-MAP kinase antibody, suggesting that the stretching mainly increased the 42-kDa MAP kinase activity in cardiac myocytes; 3) phosphorylation of MAP kinase was induced after stretching cardiac myocytes; 4) when protein kinase C was depleted by preincubating myocytes with 100 nM 12-O-tetradecanoyl-phorbol-13-acetate for 24 h or 2 nM staurosporine for 30 min, stretch-induced MBP kinase activity was decreased by approximately 60-70% as compared with the kinase activity in myocytes without protein kinase C depletion; 5) although the receptor tyrosine kinases were depleted by preincubating myocytes with 50 microM tyrphostin or 20 microM genistein for 30 min, there was no change in the stretch-induced MBP kinase activity; 6) stretch-induced MBP kinase activity was partially dependent on transsarcolemmal influx of Ca2+; 7) myocyte stretching also increased S6 peptide (RRLSSLRA) kinase activity in the anti-S6 kinase II antibody immunoprecipitates. From these results, we conclude that myocyte stretching increases the activities of MAP kinase and S6 peptide kinase, which may play an important role in the induction of the specific genes and the increase in the protein synthesis.
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PMID:Mechanical loading activates mitogen-activated protein kinase and S6 peptide kinase in cultured rat cardiac myocytes. 768 31

The proto-oncogene c-kit is allelic with the white spotting locus (W) on mouse chromosome 5 and it encodes a transmembrane protein tyrosine kinase which belongs to the platelet-derived growth factor and macrophage-colony stimulating factor (CSF-1) receptor subfamily. In an effort to study the function of the c-kit receptor, specifically the physiological mechanism of controlling the signal induced by the ligand, the effect and mechanism of down-regulation of the c-kit receptor by the kit ligand (KL) was investigated in mast cells. Following preincubation with KL, the capacity of mast cells to bind kit antibody was reduced and binding of radiolabeled KL to mast cells decreased with similar kinetics, suggesting that KL stimulates the loss of c-kit receptor from the cell surface. After binding to the c-kit receptor, KL was rapidly internalized, and degradation of the receptor was accelerated. The c-kit receptor was transmodulated by the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA) and by the calcium ionophore ionomycin. TPA- and ionomycin-induced down-regulation of the c-kit receptor was accompanied by release of the extracellular domain of the receptor, presumably by proteolytic cleavage near the transmembrane domain. Release of the extracellular domain of the c-kit receptor occurred also in untreated cells but at a slow rate. In addition, ionomycin induced shedding of the intact c-kit receptor. In mast cells depleted of protein kinase C, the c-kit receptor remained sensitive to down-regulation induced by KL and ionomycin, but not by treatment with TPA. Therefore, the down-regulation of the c-kit receptor induced by KL, activated protein kinase C, and an increased level of intracellular calcium is mediated through independent mechanisms.
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PMID:Mechanism of kit ligand, phorbol ester, and calcium-induced down-regulation of c-kit receptors in mast cells. 768 52

The product of the c-kit proto-oncogene, denoted Kit/SCF-R, encodes a tyrosine kinase receptor for stem cell factor (SCF). Kit/SCF-R induces proliferation, differentiation or migration of cells within the hematopoietic, gametogenic and melanogenic lineages at different developmental stages. We report here that protein kinase C (PKC) mediates phosphorylation of Kit/SCF-R on serine residues in response to SCF or PMA in intact cells. The phosphorylation inhibits SCF-induced tyrosine autophosphorylation of Kit/SCF-R. In vitro studies showed that PKC phosphorylated the Kit/SCF-R directly on serine residues and inhibited autophosphorylation of Kit/SCF-R, as well as its kinase activity towards an exogenous substrate. The PKC-induced phosphorylation did not affect Kit/SCF-R ligand binding affinity. Inhibition of PKC led to increased SCF-induced tyrosine autophosphorylation, as well as increased SCF-induced mitogenicity. In contrast, PKC was necessary for SCF-induced motility responses, including actin reorganization and chemotaxis. Our data suggest that PKC is involved in a negative feedback loop which regulates the Kit/SCF-R and that the activity of PKC determines whether the effect of SCF will be preferentially mitogenic or motogenic.
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PMID:Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C. 769 53

We have analyzed the relationship between the signaling pathways coupled to surface immunoglobulin and interleukin (IL)-4 receptors in human B cells from the patterns of expression of a panel of phorbol ester-inducible early response genes (ERG) activated by anti-IgM and IL-4 stimulation in vitro. Anti-IgM stimulation led to the induction of all eleven ERG tested. Two of these, the proto-oncogene, c-fos and an anonymous ERG 1R20 were insensitive to protein kinase C (PKC) inhibition with the drug, staurosporine and retained inducibility after down-regulation of PKC activity by purging with phorbol ester. These observations are consistent with previous data showing anti-IgM signaling through both PKC-dependent and PKC-independent pathways. c-fos and 1R20 were also the only ERG inducible in response to IL-4 stimulation and whilst ionomycin induced only c-fos, dibutyryl cyclic adenosine monophosphate stimulation led to induction of both c-fos and 1R20. These observations lend support to a role for the adenylate cyclase pathway being important for coupling of IL-4-generated signals to B cells responses. None of the anti-IgM-responsive ERG was further induced when B cells were co-stimulated with a combination of anti-IgM and IL-4, suggesting that the signaling cascades from these two agents are integrated downstream of third messenger pathways to synergistically promote B cell proliferation.
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PMID:Multiple signaling pathways mediate anti-Ig and IL-4-induced early response gene expression in human tonsillar B cells. 769 80

We previously reported that ACTH, but not dibutyryl cAMP, rapidly induces the c-fos proto-oncogene in Y-1 adrenocortical cells. Here we show that PMA induces c-fos with similar kinetics when compared with ACTH (0.5-1 h peak) but reaches only 60% of the maximal ACTH induction and dcAMP is a weak c-fos inducer (15% of ACTH). However, combination of PMA and dcAMP has a synergistic effect leading to maximal c-fos induction. c-fos expression may play a role in the RNA synthesis-dependent corticosteroidogenesis response and/or growth regulation by ACTH. We also show that, in contrast to dcAMP, PMA is a poor steroidogenesis stimulator (15 to 17% of maximum ACTH-stimulated level), its activity being completely dependent on RNA synthesis. Combination of dcAMP and PMA yields an additive steroidogenesis stimulation, an effect that is also dependent on RNA synthesis. Although no strict correlation was found between c-fos induction and early steroidogenesis stimulation, particularly with respect to cAMP derivatives, the results suggest that a PKC pathway is likely to cooperate with the classical cAMP-PKA pathway in adrenal cells' RNA-dependent steroidogenesis.
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PMID:Relevance of c-fos proto-oncogene induction for the steroidogenic response to ACTH, dcAMP and phorbol ester in adrenocortical cells. 769 73

B-1 lymphocytes constitute a mature B cell population that differs from conventional B cells in signaling requirements for cell cycle progression, being unusually responsive to PKC agonism but refractory to antigen receptor stimulation. Further, B-1 cells are self-renewing and derive from surface immunoglobulin-positive precursors. A previous report on clonally derived B-1 cells suggested that increased levels of expression of c-myc might underlie these unusual growth characteristics. This issue has now been reexamined using primary B-1 cells. The possible role of egr-1, in addition to c-myc, in specifying the responsiveness of B-1 cells was evaluated by determining levels of gene expression at baseline and after mitogenic treatment. Expression of the two genes was similar in B-1 and B-2 cells prior to stimulation. Subsequently, B-1 cells responded with higher levels of gene expression than B-2 cells regardless of ultimate cell cycle progression, with the exception of stimulation by anti-Ig. Overall, there was no apparent direct correlation between stimulated levels of expression of egr-1 or c-myc and mitogen-induced S phase entry, nor were B-1 cells characterized by constitutively elevated levels of either proto-oncogene that might explain their capacity for self-renewal.
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PMID:Constitutive and inducible levels of egr-1 and c-myc early growth response gene expression in self-renewing B-1 lymphocytes. 774 59

Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide which shares structural domains with enzymes of the blood clotting cascade. HGF/SF is secreted by cells of mesodermal origin and has powerful mitogenic, motogenic and morphogenic activity on epithelial and endothelial cells. HGF/SF is produced as a biologically inactive single-chain precursor (pro-HGF/SF) most of which is sequestered on the cell surface or bound to the extracellular matrix. Maturation into the active alpha beta heterodimer results from proteolytic cleavage by a urokinase-type protease, which acts as a pro-HGF/SF convertase. The primary determinant for receptor binding appears to be located within the alpha-chain. The interaction of the alpha-chain with the receptor is sufficient for the activation of the signal cascade involved in the motility response. However, the complete HGF/SF protein seems to be required to elicit a mitogenic response. HGF/SF binds with high affinity to a transmembrane receptor, p190MET, encoded by the MET proto-oncogene. p190MET is the prototype of a distinct subfamily of heterodimeric tyrosine kinases, including the putative receptors Ron and Sea. The mature form of p190MET is a heterodimer of two disulfide-linked subunits (alpha and beta). The alpha-subunit is extracellular and heavily glycosylated. The beta-subunit consists of an extracellular portion involved in ligand binding, a membrane spanning segment, and a cytoplasmic tyrosine kinase domain. Both subunits derive from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. In polarized epithelial cells the HGF/SF receptor is selectively exposed in the basolateral plasmalemma, where it is associated with detergent-insoluble components. Two Met isoforms, carrying an intact ligand binding domain but lacking the kinase domain due to truncation of the beta-subunit, arise from alternative post-transcriptional processing of the mature form. One truncated form is soluble and released from the cells. HGF/SF binding triggers tyrosine autophosphorylation of the receptor beta-subunit. Autophosphorylation on the major phosphorylation site Y1235 upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. Negative regulation of the kinase activity occurs through phosphorylation of a unique serine residue (S985) located in the juxtamembrane domain of the receptor. This phosphorylation is triggered by two distinct pathways involving either protein kinase C activation or increase in intracellular Ca2+ concentration. Upon ligand binding, the HGF/SF receptor recruits and activates several cytoplasmic effectors, including phosphatidylinositol 3-kinase (PI 3-K), phospholipase C-gamma (PLC-gamma), pp60c-Src, a tyrosine phosphatase, and a Ras-guanine nucleotide exchanger.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering. 776 52


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