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)

Bombesin is a potent mitogen for Swiss 3T3 cells and acts synergistically with insulin and other growth factors. We show here that addition of bombesin to quiescent Swiss 3T3 cells causes a striking increase in the levels of c-fos and c-myc mRNAs. Enhanced expression of c-fos (122 +/- 14-fold) occurred within minutes of peptide addition followed by increased expression of c-myc (82 +/- 16-fold). The concentrations of peptide required for half-maximal increase in the levels of c-fos and c-myc mRNAs were 1.0 and 0.9 nM, respectively. The peptide [D-Arg1, D-Pro2, D-Trp7,9, Leu11] substance P which inhibits the binding of bombesin to its receptor and bombesin-stimulated DNA synthesis in Swiss 3T3 cells blocked the increase in c-fos and c-myc mRNA levels promoted by bombesin. Down-regulation of protein kinase C by long-term exposure to phorbol esters prevented c-fos and c-myc induction by bombesin. This and other results indicate that the induction of these proto-oncogenes by bombesin could be mediated by the coordinated effects of protein kinase C activation and Ca2+ mobilization. The marked synergistic effect between bombesin and insulin was used to assess whether the increase in the induction of c-fos and c-myc is an obligatory event in cell activation. In the presence of insulin, bombesin stimulated DNA synthesis at subnanomolar concentrations but had only a small effect on c-fos and c-myc mRNA levels. This apparent dissociation of mitogenesis from proto-oncogene induction was even more dramatic in 3T3 cells with down-regulated protein kinase C. In these cells bombesin stimulated DNA synthesis in the presence of insulin but failed to enhance c-fos and c-myc mRNA levels at comparable concentrations. Thus, the induction of c-fos and c-myc may be a necessary step in the mitogenic response initiated by ligands that act through activation of protein kinase C but the expression of these proto-oncogenes may not be an obligatory event in the stimulation of mitogenesis in 3T3 cells by mitogens that utilise other signalling pathways.
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PMID:Bombesin induction of c-fos and c-myc proto-oncogenes in Swiss 3T3 cells: significance for the mitogenic response. 310 67

Epidermal growth factor (EGF) binds with high affinity and specificity to a single site on the external domain of its transmembrane receptor to activate the tyrosine protein kinase activity of its cytoplasmic portion. The EGF receptor gene is amplified and over-expressed in several human tumors, suggesting that increased concentrations of the proto-oncogene leads to constitutive activity similar to that seen with oncogene erb B. Synthesis and degradation of the EGF receptor are regulated, in addition, covalent modification by phosphorylation regulates activity of the receptor protein. Intramolecular self-phosphorylation of Tyr1173 removes a competitive inhibitory constraint to enhance phosphorylation of substrates. Phosphorylation of Thr654 by protein kinase C decreases high affinity EGF binding and EGF-stimulated tyrosine protein kinase activity, providing a mechanism for heterologous regulation of the EGF receptor by tumor promoters and other ligand X receptor complexes. Extensive regulation contributes to normal growth control, abrogation of regulatory controls contributes to uncontrolled growth as seen with erb B transformation and EGF receptor gene amplification in human tumors.
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PMID:Epidermal growth factor and its receptor. 310 78

We have investigated the covalent modification of the proteins encoded by the murine fos proto-oncogene (c-fos) and that of the corresponding gene product of FBJ murine osteosarcoma virus (v-fos). Both proteins are posttranslationally processed in the cell, resulting in forms with lower electrophoretic mobilities than that of the initial translation product on sodium dodecyl sulfate-polyacrylamide gels. Treatment with alkaline phosphatase indicates that most, if not all, of this electrophoretic shift is due to phosphoesterification of both proteins. These phosphoryl groups stoichiometrically modify the v-fos and c-fos proteins on serine residues and turn over rapidly in vivo in the presence of protein kinase inhibitors (half-life, less than 15 min). Direct quantitative comparison of steady-state labeling studies with L-[35S]methionine and [32P]phosphate reveals that the c-fos protein is four- to fivefold more highly phosphorylated than the v-fos protein is. Comparison of tryptic fragments from [32P]phosphate-labeled proteins indicates that although the two proteins have several tryptic phosphopeptides in common, the c-fos protein contains unique major tryptic phosphopeptides that the v-fos protein lacks. These unique sites of c-fos phosphorylation have been tentatively localized to the carboxy-terminal 20 amino acid residues of the protein. Phosphorylation of the c-fos protein, but not the v-fos protein, can be stimulated at least fivefold in vivo by the addition of either 12-tetradecanoyl-phorbol-13-acetate or serum. This increase in the steady-state degree of phosphorylation of c-fos appears to be independent of protein kinase C since phosphorylation is Ca2+ and diacylglycerol independent. The possible role of phosphorylation of these proteins in cellular transformation is discussed.
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PMID:Modification of fos proteins: phosphorylation of c-fos, but not v-fos, is stimulated by 12-tetradecanoyl-phorbol-13-acetate and serum. 311 Jun 3

The chemotactic peptide, fMet-Leu-Phe (fMLP), induced proto-oncogene c-fos mRNA in purified human peripheral granulocytes. The induction was transient, and was inhibited by pertussis toxin or by an inhibitor of protein kinase C. These results suggest that activation of a guanine nucleotide-binding protein and of protein kinase C is involved in c-fos induction in granulocytes.
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PMID:Induction of c-fos proto-oncogene by a chemotactic peptide in human peripheral granulocytes. 311 32

Control of entry into and progression through the early phases of cell cycle in B lymphocytes is poorly understood at the molecular level. Products of the c-fos proto-oncogene have been implicated in regulation of G0 to G1 cell cycle phase transition and cell proliferation in other systems. In view of these observations, the relationship between signals generated through receptor Ig which alter the B cells position in cell cycle and relative level of c-fos expression was investigated. Not unexpectantly, anti-Ig under conditions which promote G0-G1 and G1-S phase transition was observed to selectively up-regulate expression of c-fos. More interestingly, however, anti-Ig-induced cross-linking of surface Ig on the WEHI-231 B lymphoma also caused rapid and transient up-regulation of c-fos mRNA levels although it was associated with inhibition of proliferation of these cells. These results are important because they show that 1) c-fos expression is inducible in both normal and transformed B lymphocytes as a consequence of signals generated through receptor Ig, and 2) up-regulation of c-fos expression is not positively linked to B cell proliferation but rather appears to be a component of the surface Ig signal transduction mechanism. Finally, studies utilizing phorbol diesters suggest that pathways leading through protein kinase C are involved in both the growth inhibition and c-fos expression WEHI-231 following membrane-associated Ig cross-linking.
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PMID:Up-regulation of c-fos expression is a component of the mIg signal transduction mechanism but is not indicative of competence for proliferation. 312 26

In order to analyse the molecular mechanism of lymphocyte activation defect in MRL/MP-lpr (MRL/1) mice, c-myc proto-oncogene expression was examined in MRL/1 lymph node cells stimulated by various agents. Since a transient increase of c-myc RNA in early hours is required for lymphocyte activation, detection of c-myc messenger RNA is useful to determine whether or not an appropriate signal is transduced to the nucleus. Stimulation by concanavalin A (Con A) plus 12-O-tetradecanoyl phorbol 13-acetate (TPA) or A23187 plus TPA markedly increased c-myc mRNA expression and cell proliferation, whereas stimulation by Con A alone failed to do so. These results suggest that an abnormality exists in the early signal transduction process, and that it could be bypassed by calcium influx and direct activation of protein kinase C.
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PMID:C-myc expression in lymphocytes of MRL/MP-lpr mice activated by A23187 and TPA. 313 10

The regulation of expression of the TCR-alpha and -beta genes was studied in the human T cell tumor line Jurkat. Treatment of the cells with PMA was shown to decrease the surface expression of the TCR-alpha/beta/CD3 complex. Subsequent to PMA-induced modulation of the TCR/CD3 complex, increases in the mRNA levels of both the TCR-alpha and -beta genes were observed reaching a maximum 12 h after stimulation. Other T cell activators were also examined for their ability to increase TCR-alpha and -beta mRNA expression. Only agents that activate protein kinase C were shown to induce expression of the TCR-alpha and -beta genes. The observed increases in TCR-alpha and -beta gene mRNA levels were not the result of a uniquely derived Jurkat subline. Similar inductions of TCR-alpha and -beta mRNA levels were observed in an independently maintained Jurkat cell line. In both cell lines, elevations of TCR gene expression was accompanied by a decline in the expression of the c-myc proto-oncogene. PMA induction of TCR-alpha and -beta mRNA was shown to occur in the presence of the protein synthesis inhibitor cycloheximide. The 1.6-kb TCR-alpha and the 1.0-kb D beta J beta C beta TCR-beta gene transcripts were fully induced in the presence of cycloheximide, whereas the 1.3-kb V beta D beta J beta C beta transcript was only partly induced in the presence of cycloheximide. Run-on transcription assays demonstrated that the increase in TCR-alpha and -beta mRNA levels could be entirely accounted for by increases in the transcription rate of both genes after PMA induction. Thus, in summary, protein kinase C stimulation leads to TCR-alpha/beta modulation in Jurkat cells and an increase in steady state TCR-alpha and -beta mRNA levels as a result of transcriptional activation of both genes.
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PMID:Transcription of T cell antigen receptor genes is induced by protein kinase C activation. 326 60

We evaluated the mechanism of insulin and phorbol ester induction of the proto-oncogene c-fos in Chinese hamster ovary fibroblasts stably transformed with high levels of genes expressing normal or truncated human insulin receptors. Both insulin and the tumor-promoting phorbol ester phorbol 12-myristate 13-acetate (PMA) induced c-fos mRNA accumulation in cells expressing high numbers of normal human insulin receptors; PMA but not insulin was effective in the cells expressing the mutant receptor. Transient expression studies with plasmid constructions containing c-fos 5'-flanking sequences ligated to the bacterial chloramphenicol acetyltransferase gene indicated that sequences corresponding to the serum response element were required for induction of c-fos transcription by both insulin and PMA. The insulin-sensitive cells contained a nuclear factor, presumably a protein, which bound specifically to this sequence of the c-fos gene; the apparent affinity of this factor to the normal serum response element was not affected by prior treatment of the cells with insulin or PMA. This c-fos binding factor may prove to be important in the regulation of c-fos expression by insulin and activators of protein kinase C.
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PMID:Identification of c-fos sequences involved in induction by insulin and phorbol esters. 327 73

The complete primary structure of the protein product of the proto-oncogene c-mil was deduced from the nucleotide sequence of chicken c-mil cDNA clones. The c-mil protein contains 647 amino acid residues and has a calculated molecular weight of 73,132. Based on sequence comparisons with proteins of known or presumed biochemical function, two domains were recognized on the c-mil protein. In the carboxyl-terminal half of the protein, a 250-amino acid segment displays significant homology to the protein kinase domains of the src oncogene protein or of protein kinase C. In the amino-terminal half, a cysteine-rich segment (Cys-X2-Cys-X9-Cys-X2-Cys-X7-Cys-X7-Cys) of the c-mil protein shares significant homology with two similar repetitive domains of protein kinase C. Of the two structural and presumably functional domains of the c-mil protein, only the kinase domain is contained within the carboxyl-terminal 379-amino acid polypeptide encoded by the transduced v-mil allele of avian oncogenic retrovirus MH2. Hence, truncation of the 5' coding region in the course of the transduction and the resulting lack of the authentic amino-terminal domain in the protein product of the transduced allele may be a critical event in changing mil function from physiologic to oncogenic.
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PMID:Primary structure of the chicken c-mil protein:identification of domains shared with or absent from the retroviral v-mil protein. 328 96

MELC may be induced to terminal erythroid differentiation by HMBA and other agents. Although the mechanism is not known, changes in cell function and gene expression can be identified during an early "latent" period, prior to commitment to terminal differentiation. These include a decrease in diacylglycerol concentration and in Ca+2 and phospholipid-dependent protein kinase C activity, accompanied by suppression of c-myb and c-myc gene transcription, a fall in p53 protein, and an increase in c-fos mRNA. Commitment is first detected by 12 hours and is associated with persistent suppression of c-myb gene transcription. Transcription of the erythroid-specific genes, alpha 1 and beta maj globin, is increased 10- to 30-fold, whereas synthesis of rRNA is suppressed, and there is activation or suppression of a number of additional genes that remain to be characterized. The potential regulatory roles of changes in protein kinase C activity and in proto-oncogene expression in initiating and sustaining the process of differentiation also remain to be elucidated.
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PMID:Induced erythroleukemia differentiation: cellular and molecular aspects. 331 Dec 22


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