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)

The c-myc gene encodes a sequence-specific DNA-binding protein (c-Myc) that forms leucine zipper complexes and can act as a transcription factor. Growth factor stimulation of cells causes the phosphorylation of the c-Myc transcriptional activation domain at Ser62 within a proline-rich region that is highly conserved among members of the Myc family (Alvarez, E., Northwood, I.C., Gonzalez, F. A., Latour, D. A., Seth, A., Abate, C., Curran, T., and Davis, R. J. (1991) J. Biol. Chem. 266, 15277-15285). This phosphorylation site is a substrate for growth factor-regulated MAP kinases and for the cell cycle-dependent protein kinase p34cdc2. We report that serum treatment of cells results in a marked increase in the transactivation of gene expression mediated by the c-Myc transcriptional activation domain. A point mutation at the site of growth factor-stimulated phosphorylation (Ser62) decreases the serum induction of transactivation. These data indicate that the c-Myc transcriptional activation domain may be a direct target of signal transduction pathways.
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PMID:A phosphorylation site located in the NH2-terminal domain of c-Myc increases transactivation of gene expression. 174 30

Occupancy of surface immunoglobulin (sIg) receptor for antigen expressed on resting B cells initiates increased turnover of membrane-associated phosphatidylinositol (PI), which ultimately leads to the enhanced expression of c-myc mRNA. The mechanism which links these initial membrane biochemical changes to subsequent alterations in c-myc transcription is unclear. The present study examines the possible involvement of PKC and its calpain-generated proteolytic fragment, protein kinase M (PKM), in conveying the membrane-associated signal to the nucleus. Utilizing an in vitro phosphorylation assay, we have shown that a calcium-dependent protease, similar to calpain, is involved in the downregulation of membrane-associated PKC induced by anti-immunoglobulin or phorbol 12-myristate 13-acetate (PMA) and ionomycin stimulation of resting B cells. In addition, we have confirmed previous studies showing that PMA and ionomycin are both required for optimal expression of c-myc mRNA. The enhanced expression of c-myc mRNA is sensitive to inhibitors of PKC, such as H-7 and sangavimycin, providing evidence for a prominent role of PKC and/or PKM in the receptor-mediated up-regulation of c-myc message expression. Finally, a calpain inhibitor interferes with the transmission of the membrane-associated signal which induces the increased expression of c-myc mRNA. Our results are consistent with the hypothesis that the calpain-mediated proteolysis of membrane-associated PKC is involved in the sIg-mediated signal transduction pathway.
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PMID:The proteolysis of membrane-associated protein kinase C as a possible component of the signalling pathway leading to c-myc induction in B lymphocytes. 176 Feb 54

Proteins encoded by the proto-oncogenes c-myc, L-myc, and N-myc contain at their carboxy-terminus a tripartite segment comprising a basic DNA binding region (BR), a helix-loop-helix (HLH) and a leucine zipper motif (Zip), that are believed to be involved in DNA binding and protein-protein interaction. The N-Myc oncoprotein is overexpressed in certain human tumors that share neuroectodermal features due to amplification of the N-myc gene. Using a monoclonal antibody directed against an N-terminal epitope of the N-Myc protein in immunoprecipitations performed with extracts of neuroblastoma cells, two nuclear phosphoprotein, p20/22, forming a hetero-oligomeric complex with N-Myc are identified. Both proteins are phosphorylated by casein kinase II in vitro. By partial proteolytic maps we show that p20 and p22 are structurally related to each other and that p20 is identical with Max, a recently described in vitro binding partner of myc proteins. Time course experiments show the presence of the complex in cellular extracts immunoprecipitated within a 5 min interval after the preparation of the cell extract. While the expression of N-myc is restricted, expression of both Max(p20/22) and the murine homolog Myn(p20/22) was observed in cells of diverse human and murine embryonal lineages as detected by heterologous complex formation. By introduction of expression vectors containing the wild type N-myc gene or N-myc genes with in frame deletions or point mutations into recipient cells and subsequent immunoprecipitation of the resulting N-Myc proteins we show that the HLH-Zip region is essential to the formation of the N-Myc-p20/22 complex.
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PMID:The N-Myc oncoprotein is associated in vivo with the phosphoprotein Max(p20/22) in human neuroblastoma cells. 193 96

Rat-1 cells infected with a temperature sensitive mutant of RSV (ts LA 29 Rat-1) can be rendered quiescent by serum deprivation at restrictive temperature. Shift to permissive conditions activates the v-src protein tyrosine kinase within 10 minutes and either this stimulus, or serum addition at restrictive temperature, leads to progression of the cell from G0 to G1, S-phase and mitosis. The effects of serum and temperature shift are not synergistic, suggesting that they may operate by convergent mechanisms. However, the characteristic serum-stimulated transient increases in transcripts of three immediate early response genes, c-fos, c-jun and c-myc are absent or much reduced when mitogenesis in ts LA 29 Rat-1 is induced by pp60v-src. Nonetheless, upon activating the pp60v-src protein kinase there is a marked and rapid increase in the ability of ts LA 29 Rat-1 nuclear extracts to retard the gel migration of oligonucleotides containing the AP-1 binding site, indicating that pp60v-src activity leads to an enhanced functioning of Fos and Jun related proteins that may, in turn, affect their transcriptional activation. Furthermore, these findings, and comparison with those of other laboratories, suggest that the mitogenic and transforming activities of pp60v-src have different effects on the transcription of immediate early response genes.
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PMID:Mitogenesis induced by pp60v-src is not accompanied by increased expression of immediate early response genes. 210 4

HL-60 cells were derived from a patient with myelocytic leukemia, and are known to be in the promyelocytic stage and to differentiate into myelocytes or granulocytes after induction with several materials, e.g., DMSO, retinoic acid, and interferons. The authors intended in this report to determine whether asbestos fibers have any effect on the differentiation processes of HL-60 cells induced with DMSO. The cells were induced to differentiate by incubation with 1.25% DMSO for 4 days. A decrease in the percentage of c-myc-protein-positive cells and an increase in the number of C3bi receptor (CD11b) positive cells were observed after differentiation. When crocidolite (50 micrograms/ml) was added to the culture dishes at the beginning of the experiments, the differentiation was inhibited. An increase in the percentage of c-myc-protein-positive cells and a decrease in that of C3bi-receptor-positive cells were observed compared with the cells induced with DMSO alone. It has been reported that DMSO activates phospholipid- and Ca2(+)-dependent protein kinase and induces the differentiation of HL-60 cells. The mechanisms of inhibition by crocidolite fibers of the effects of DMSO remain to be clarified, but the strength of activation of phospholipid- and Ca2(+)-dependent protein kinase may play an important role in the following induction of cell differentiation.
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PMID:[Suppressive effect of crocidolite fibers on the differentiation of HL-60 cells induced with DMSO]. 216 2

Phorbol esters induce the human HL-60 promyelocytic cell line to differentiate along a monocytic pathway. This induction of differentiation may involve phorbol ester-induced activation of the phospholipid- and calcium-dependent protein kinase C. Bryostatin 1, a macrocyclic lactone, has been shown to compete with phorbol esters for binding to protein kinase C. We have confirmed that bryostatin 1 translocates activity of protein kinase C from the cytosolic to membrane fractions of HL-60 cells. The present results also demonstrate that bryostatin 1 (10 nmol/L) induces monocytic differentiation of HL-60 cells as determined by adherence, growth inhibition, appearance of monocyte cell surface antigens, and alpha-naphthyl acetate esterase staining. Furthermore, bryostatin 1 (10 nmol/L) downregulated c-myc expression and induced c-fos, c-fms, and tumor necrosis factor transcripts. These changes in gene expression induced by bryostatin 1 are similar to those associated with phorbol ester-induced monocytic differentiation of HL-60 cells. In contrast, exposure to a higher concentration of bryostatin 1 (100 nmol/L) had less of an effect on growth inhibition of HL-60 cells and changes in gene expression. Moreover, 100 nmol/L bryostatin 1 antagonized the cytostatic effects and adherence induced by phorbol esters. Our results thus suggest that bryostatin 1 activates HL-60 cell protein kinase C and that this effect is associated with induction of monocytic differentiation.
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PMID:Bryostatin 1 activates protein kinase C and induces monocytic differentiation of HL-60 cells. 245 68

The peripheral blood mononuclear cells from patients with B-chronic lymphocytic leukemia (B-CLL) were incubated for 0.5 h to 72 h in the presence of the phorbol ester TPA, the calcium ionophore A23187, or a combination of these reagents. Using Northern blot analysis, total cellular RNA was prepared from cells harvested at different time points and hybridized with DNA clones specific for the protooncogenes c-fos and c-myc. While untreated control cells lacked detectable amounts of messenger RNA (mRNA), increase in the level of c-fos mRNA was noted as early as 0.5 h after exposure to the inducers. Peaks of c-fos and c-myc transcript accumulation were seen at 1 h and 4 h after induction, respectively. The most effective inducer was double stimulation with TPA plus A23187. The kinetics of c-fos and c-myc mRNA accumulation in B-CLL appear to be similar to those reported for normal lymphocytes that have been either activated by physiologic external stimuli or by direct activators of protein kinase C and calcium flux (such as TPA and A23187). No direct link between oncogene expression and proliferation or differentiation parameters could be established. These results document that expression of c-fos and c-myc genes, which are among the earliest events following stimulation of the protein kinase signal transduction pathway, can be successfully induced in B-CLL cells. The data provide further evidence for the hypothesis that signal transmission downstream of protein kinase C is intact in B-CLL.
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PMID:Rapid expression of protooncogenes c-fos and c-myc in B-chronic lymphocytic leukemia cells during differentiation induced by phorbol ester and calcium ionophore. 249 72

Phorbol 12-myristate 13-acetate (PMA) can induce transcription of a number of "early" genes in quiescent fibroblasts, although the biochemical steps intervening between activation of protein kinase c and changes in gene-regulatory proteins are only partially known. To investigate these pathways further, we have studied the effect of indomethacin (INDO) on the induction of expression by PMA of three early genes (c-fos, egr-1 and c-myc) in quiescent BALB/c 3T3 cells. INDO was found to markedly change the kinetics of PMA-induced c-fos and egr-1 gene expression, as measured by Northern analysis. As opposed to the normal peak of mRNA at 30 min and 30-60 min for c-fos and egr-1, respectively, the appearance of each peak in the presence of INDO was delayed by 30-60 min, although the amount of mRNA was approximately normal. By contrast, c-myc mRNA levels remained low for at least 3 hr. This effect on gene expression required concentrations of INDO (0.25-1 mM) which have previously been shown to inhibit cAMP-dependent protein kinases. The effect was reversible: after 75 min treatment with INDO followed by removal of the drug, c-fos was induced with normal kinetics by PMA. Cycloheximide superinduced the expression of c-fos, egr-1 and c-myc after PMA treatment; INDO inhibited this superinduction. Although its mode of action is not yet defined, the ability of INDO to perturb the kinetics of expression 3 PMA-inducible genes may make it a useful drug to study the signal transduction pathways involved in gene induction.
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PMID:Indomethacin shifts the peak of c-fos, egr-1, and c-myc gene expression in confluent fibroblasts induced by phorbol myristate acetate. 250 Jan 19

Two classes (site 1- and site 2-selective) of cAMP analogs, which either alone or in combination demonstrate a preference for binding to type II rather than type I cAMP-dependent protein kinase isozyme, potently inhibit growth in a spectrum of human cancer cell lines in culture. Treatment of K-562 human leukemic cells for 3 days with 30 and 10 microM 8-chloroadenosine 3',5'-cyclic monophosphate (8-Cl-cAMP) (site 1-selective) resulted in 60% and 20% growth inhibition, respectively (with over 90% viability). N6-Benzyl-cAMP (site 2-selective) (30 microM) treatment resulted in 20% growth inhibition by day 3. When 8-Cl-cAMP (10 microM) and N6-benzyl-cAMP (30 microM) were both added, growth was almost completely arrested. The growth inhibition was accompanied by megakaryocytic differentiation in K-562 cells. The untreated control cells expressed little or no detectable levels of glycoprotein IIb-IIIa surface antigen complex. 8-Cl-cAMP (30 microM) treatment for 3 days substantially increased the antigen expression, while N6-benzyl-cAMP caused little or no change in the antigen expression. When cells were treated with 8-Cl-cAMP in combination with N6-benzyl-cAMP, antigen expression was synergistically enhanced, and cells demonstrated megakaryocyte morphology. By Northern blotting, we examined the mRNA levels of the type I and type II protein kinase regulatory subunits (RI alpha and RII beta), the catalytic subunit, and c-myc during 8-Cl-cAMP treatment. The steady-state level of RII beta cAMP receptor mRNA sharply increased within 1 hr of treatment and remained elevated for 3 days, while that of the RI alpha receptor markedly decreased to below control level within 6 hr and remained low during treatment. However, 8-Cl-cAMP did not affect the mRNA level of the catalytic subunit. 8-Cl-cAMP treatment also brought about a rapid decrease in c-myc mRNA. Thus, differential regulation of cAMP receptor genes is an early event in cAMP-induced differentiation and growth control of K-562 leukemia cells.
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PMID:Induction of megakaryocytic differentiation and modulation of protein kinase gene expression by site-selective cAMP analogs in K-562 human leukemic cells. 253 2

Alteration of oncogene and loss of chromosomal heterozygosity are infrequent in human gastric carcinoma compared with those in other gastrointestinal carcinomas. Amplification of c-erbB-2 gene is observed in well differentiated adenocarcinoma, while sam gene is found in poorly differentiated adenocarcinoma or scirrhous carcinoma. sam gene, which was isolated from a gastric cancer cell line KATO-III by a DNA renaturation method, encodes tyrosine-specific protein kinase domain. A good correlation evidently exists between the synchronous expression of TGF alpha and ras p21 and biological malignancy of gastric carcinoma. c-myc and c-fos proteins are found not only in tumor cells but also in stromal cells including macrophages and fibroblast around the tumors. The prognosis of patients with c-myc p 62-positive stromal cells is significantly better than that of patient with p 62-negative stromal cells. Coamplification of the hst-1 gene and int-2 is observed in 50% of primary tumors and all metastatic tumors of esophageal carcinoma. PCR (polymerase chain reaction) technique seems to be useful for the detection of oncogene point mutation in human gastric carcinoma.
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PMID:[Oncogenes in human gastric carcinoma]. 254 46


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