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)

p21c-ras plays a critical role in mediating tyrosine kinase-stimulated cell growth and differentiation. However, the pathways through which p21c-ras propagates these signals remain unknown. We report that in PC12 cells, expression of a dominant inhibitory mutant of ras, c-Ha-ras(Asn-17), antagonizes growth factor- and phorbol ester-induced activation of the erk-encoded family of MAP kinases, the 85-92 kd RSKs, and the kinase(s) responsible for hyperphosphorylation of the proto-oncogene product Raf-1. In addition, we find that expression of the activated ras oncogene is sufficient to stimulate these events. These data indicate that ras mediates nerve growth factor receptor and protein kinase C modulation of MAP kinases, RSKs, and Raf-1.
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PMID:ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. 131 93

The commitment of myogenically determined cells to terminal differentiation can be modulated by a variety of agents, including growth factors and activated oncogenes. We have examined the effect of interleukin 1 alpha (IL-1 alpha) on the terminal differentiation of a normal myogenically determined cell line and two myogenically determined, differentiation competent cell lines which contain either one or six copies of the activated c-Ha-ras oncogene. Treatment of all cell lines with IL-1 alpha decreased but did not totally inhibit terminal myogenic differentiation. Over the range of IL-1 alpha concentrations assayed (1-40 ng/ml), the c-Ha-ras transformed cell lines demonstrated a significantly greater sensitivity to the inhibitory effects of IL-1 alpha. The inhibition of differentiation was not the result of enhanced proliferation. Interestingly, transformation with activated c-Ha-ras resulted in a decrease in IL-1 alpha receptor number and affinity. The enhanced IL-1 alpha responsiveness of the ras transformants was not the result of increased proliferation or changes in either ras gene expression or protein kinase C activity. IL-1 alpha treatment decreased the steady-state levels of both MyoD1 and myogenin transcripts in the c-Ha-ras transformed but not the normal myogenic cell line. Further studies are required to determine the mechanism(s) responsible for the increased sensitivity of the c-Ha-ras transformed cultures to the inhibitory effects of IL-1 alpha.
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PMID:Interleukin 1 alpha mediated inhibition of myogenic terminal differentiation: increased sensitivity of Ha-ras transformed cultures. 132 82

The protein kinase C (PKC) family of phospholipid-dependent serine-threonine kinases has been implicated in keratinocyte differentiation and neoplastic transformation. To determine if Ca(2+)-mediated keratinocyte differentiation is associated with changes in PKC isozyme gene expression, RNA was isolated from primary mouse keratinocytes grown in medium with 0.05, 0.12, or 1.4 mM Ca2+. Based on northern blot analysis, primary keratinocytes expressed mRNA encoding PKC-alpha, -delta, -epsilon, -zeta, and -eta, but not PKC-beta or -gamma. Relatively little change was detected in the level of these transcripts in cells induced to differentiate by exposure to elevated extracellular Ca2+. Interestingly, the PKC-zeta transcripts detected in RNA isolated from keratinocytes were approximately 200 nucleotides longer than those from mouse brain, suggesting the existence of an alternative form of this isozyme. An early change in benign neoplastic transformation of keratinocytes is the inability to differentiate in response to Ca2+ or the PKC activator 12-O-tetradecanoylphorbol-13-acetate, which is consistent with altered PKC function in these cells. The PKC isozyme mRNA profile was examined in two benign neoplastic keratinocyte cell lines, 308 and SP-1, which contain an activating mutation of the c-Ha-ras gene. Like normal keratinocytes. 308 and SP-1 cells expressed mRNA encoding PKC-alpha, -delta, -epsilon, -zeta, and -eta. However, the abundance of PKC-zeta transcripts in both cell lines was reduced by 74-89% when compared with normal keratinocytes at similar Ca2+ levels. In addition, SP-1 but not 308 cells exhibited a sevenfold increase in PKC-eta mRNA when cultured in medium with 1.4 mM Ca2+. To address whether these changes were related to the presence of an activated ras gene, RNA was isolated from primary keratinocytes transduced to a benign neoplastic phenotype with the v-Ha-ras oncogene. As with normal, 308, and SP-1 cells, v-Ha-ras keratinocytes expressed mRNA encoding PKC-alpha, -delta, -epsilon, -zeta and -eta. The level of PKC-zeta transcripts was similar in normal and v-Ha-ras keratinocytes, indicating that reduction of this mRNA in both 308 and SP-1 cells was not a direct result of ras activation. As in SP-1 cells, PKC-eta in v-Ha-ras keratinocytes was responsive to extracellular Ca2+, with a four-fold increase in transcript abundance in 0.12 mM Ca2+ medium relative to 0.05 mM Ca2+ medium.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Transcripts encoding protein kinase C-alpha, -delta, -epsilon, -zeta, and -eta are expressed in basal and differentiating mouse keratinocytes in vitro and exhibit quantitative changes in neoplastic cells. 137 14

The mouse skin model of multistage carcinogenesis has for many years provided a conceptual framework for studying carcinogenesis mechanisms and potential means for inhibiting specific stages of carcinogenesis. The process of skin carcinogenesis involves the stepwise accumulation of genetic change ultimately leading to malignancy. Initiation, the first step in multistage skin carcinogenesis involves carcinogen-induced genetic changes. A target gene identified for some skin tumor initiators is c-Ha-ras. The second step, the promotion stage, involves processes whereby initiated cells undergo selective clonal expansion to form visible premalignant lesions termed papillomas. The process of tumor promotion involves the production and maintenance of a specific and chronic hyperplasia characterized by a sustained cellular proliferation of epidermal cells. These changes are believed to result from epigenetic mechanisms such as activation of the cellular receptor, protein kinase C, by some classes of tumor promoters. The progression stage involves the conversion of papillomas to malignant tumors, squamous cell carcinomas. The accumulation of additional genetic changes in cells comprising papillomas has been correlated with tumor progression, including trisomies of chromosomes 6 and 7 and loss of heterozygosity. The current review focuses on the mechanisms involved in multistage skin carcinogenesis, a summary of known inhibitors of specific stages and their proposed mechanisms of action, and the relevance of this model system to human cancer.
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PMID:Multistage carcinogenesis in mouse skin. 152 55

The myeloid interleukin-3 (IL-3) dependent cell line, FDC-P1, enters the G0 stage of the cell cycle after IL-3 deprivation for 24 hr. The expression of 13 protooncogenes and immediate-early genes was compared with 4 "control" genes after the addition of either IL-3 or phorbol myristate acetate (PMA) to IL-3-deprived cells. mRNA transcripts encoding c-myc and the T-cell receptor c-gamma gene were induced to high levels only after IL-3 addition, whereas c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 were induced transiently only after PMA addition. The remaining genes (fra-1, p53, jun-D, c-Ha-ras, c-Ki-ras, c-raf, beta-actin, ornithine decarboxylase, and histone 2B) were detected after culture with either IL-3 or PMA. When cells were serum- and IL-3-deprived, c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 were detected after exposure to either serum or PMA. Moreover, culture with cycloheximide and PMA resulted in superinduction of these genes, whereas cycloheximide and IL-3 addition did not. mRNAs encoding these genes had half-lives of 10-20 min after PMA treatment, whereas that of beta-actin was longer (greater than 2 hr), suggesting that short mRNA half-lives contributed to the transient nature of these genes. Although c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 expression can be detected in IL-3-dependent cells after exposure to either PMA or serum, these genes were not detected after IL-3 addition, which allows cell-cycle progression. These results document the existence of IL-3 and PMA-responsive genes and demonstrate that IL-3 and protein kinase C agonists can induce distinct patterns of gene expression.
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PMID:Interleukin-3 and phorbol esters induce different patterns of immediate-early gene expression in an interleukin-3 dependent cell line. 170 18

Transformation of secondary Sprague-Dawley rat embryo (RE) cells with type 5 adenovirus (Ad5) results in morphologically transformed cells which can undergo a series of sequential changes resulting in enhanced expression of the transformed phenotype, a process termed progression. Selection for a progressed phenotype often occurs after growth in agar or tumor formation in nude mice, and this process is reversible following treatment of cells with 5-azacytidine. In the present study we have analyzed a series of clonal populations of Ad5-transformed RE cells representing different stages in a defined progression lineage. Progression was not associated with alterations in the steady-state levels of mRNA produced by the viral transforming genes, E1A and E1B, or the cellular gene, c-myc. In addition, the tumor-promoting agent 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which induces expression of a progressed phenotype in Ad5-transformed RE cells, did not significantly alter the RNA transcription rates of the Ad5 E1A or E1B genes, the TPA-inducible gene TPA-S1 or the TPA-responsive genes Pro1 or protein kinase C. TPA did, however, increase by 1 h the steady-state level of c-fos mRNA, but this effect was similar in both progressed and unprogressed cells. Progression also did not involve a change in the RNA transcription rate of a number of cellular and viral genes, including actin, c-Ha-ras, c-myc, v-fos, erbB, TGF-alpha, TGF-beta, Pro-2, transin, TPA-R1, v-myb and c-mos, or other adenovirus genes in addition to E1A and E1B, including E2A and E4. Immunoblotting analysis using E1B polyclonal antiserum further indicated that progression was not associated with changes in the levels of an Mr 21,000 polypeptide encoded by E1B. Similarly, immunoprecipitation analysis with an Ad2 E1A monoclonal antibody indicated similar levels of the Mr 55,000 and 48,000 E1A polypeptides, as well as coprecipitated proteins of Mr 300,000, 107,000 and 105,000 [which is the retinoblastoma (Rb) protein], in E11 and E11-NMT cells. Immunoprecipitation of cell lysates with a monoclonal antibody specific for the Mr 105,000 Rb protein further demonstrated that progression also was not associated with a change in the level or state of phosphorylation of the Rb protein. However, transfection of a human Rb gene (also containing a neomycin resistance gene) into Ad5-transformed RE cells was more inhibitory, with respect to formation of G418-resistant colonies, in unprogressed than in progressed Ad5-transformed RE cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Analysis of viral and cellular gene expression during progression and suppression of the transformed phenotype in type 5 adenovirus-transformed rat embryo cells. 192 6

Infection of the bone marrow-derived mast cell line PB-3c with a retrovirus carrying oncogenic c-Ha-ras or v-Ha-ras reduced the interleukin 3 (IL-3) growth requirement and induced a state of tumorigenicity. In contrast, normal c-Ha-ras had no effect on the IL-3 requirement of this cell line nor did the cells become tumorigenic. A factor reduction similar to that caused by activated Ha-ras was transiently obtained with 12-O-tetradecanoylphorbol-13-acetate in the PB-3c cells expressing normal c-Ha-ras. The analogous stimulation of protein kinase C (PKC) in PB-3c cells producing oncogenic Ha-ras led to an additional reduction of the IL-3 requirement during the first 24 h. In the absence of IL-3, the prolonged exposure of the cells to 12-O-tetradecanoylphorbol-13-acetate for 72 h resulted in a stimulation of growth when activated but not when normal Ha-ras was expressed. PB-3c cell lines expressing activated Ha-ras neither revealed differences in the amounts nor in the subcellular distribution of PKC activity but displayed elevated levels of immunoreactive beta-PKC compared to the parental PB-3c cells. Upon 12-O-tetradecanoylphorbol-13-acetate treatment, a protracted down-regulation of the immunodetectable alpha-PKC as well as constitutively high levels of c-fos mRNA were observed when oncogenic Ha-ras was expressed. These data suggest the involvement of specific PKC subtypes and of c-fos in the reduction of the IL-3 requirement caused by activated Ha-ras in this particular hematopoietic cell line.
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PMID:Tumor-promoting phorbol ester and activated Ha-ras synergistically reduce the interleukin 3 requirement in a mast cell line. 198 80

We used a dominant inhibitory mutation of c-Ha-ras which changes Ser-17 to Asn-17 in the gene product p21 [p21(Asn-17)Ha-ras] to investigate ras function in mitogenic signal transduction. An NIH 3T3 cell line [NIH(M17)] was isolated that displayed inducible expression of the mutant Ha-ras gene (Ha-ras Asn-17) via the mouse mammary tumor virus long terminal repeat and was growth inhibited by dexamethasone. The effect of dexamethasone induction on response of quiescent NIH(M17) cells to mitogens was then analyzed. Stimulation of DNA synthesis by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was completely blocked by p21(Asn-17) expression, and stimulation by serum, fibroblast growth factor, and platelet-derived growth factor was partially inhibited. However, the induction of fos, jun, and myc by EGF and TPA was not significantly inhibited in this cell line. An effect of p21(Asn-17) on fos induction was, however, demonstrated in transient expression assays in which quiescent NIH 3T3 cells were cotransfected with a fos-cat receptor plasmid plus a Ha-ras Asn-17 expression vector. In this assay, p21(Asn-17) inhibited chloramphenicol acetyltransferase expression induced by EGF and other growth factors. In contrast to its effect on DNA synthesis, however, Ha-ras Asn-17 expression did not inhibit fos-cat expression induced by TPA. Conversely, downregulation of protein kinase C did not inhibit fos-cat induction by activated ras or other oncogenes. These results suggest that ras proteins are involved in at least two parallel mitogenic signal transduction pathways, one of which is independent of protein kinase C. Although either pathway alone appears to be sufficient to induce fos, both appear to be necessary to induce the full mitogenic response.
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PMID:Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction in NIH 3T3 cells. 211 93

Pressure overload induces cardiac hypertrophy and reexpression of contractile protein isogenes. To ascertain the molecular mechanism of these events, we examined the expression of cellular oncogenes and the early change in the translational activity of specific cardiac mRNA by two-dimensional gel electrophoresis of in vitro translational products. Pressure overload increased the expression levels of c-fos, c-myc, and c-Ha-ras genes. The relative predominance of 8 species out of over 400 translational products was increased by pressure overload while that of 2 translational products was decreased. We cloned four pressure-overload-responsive cDNA clones by differential dot blot hybridization. The expression pattern of each cDNA clone in the pressure-overloaded hearts was similar to that in fetal hearts. To examine whether mechanical stimuli directly induce specific gene expression in the heart, we cultured rat neonatal cardiocytes in elastic silicone dishes and stretched these adherent cells. Myocytes stretching stimulated amino acid uptake and expression of the c-fos gene, which was blocked by protein kinase C inhibitors. These results suggest that there are some early responsive genes in cardiac hypertrophy and that mechanical loading directly stimulates gene expression possibly via protein kinase C activation.
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PMID:Molecular mechanism of cardiac hypertrophy. 214 17

Diploid WB rat liver epithelial cells contain abundant, rapidly internalized epidermal growth factor receptors, and respond pleiotropically to ligand binding. Signal transduction pathways downstream from the EGF receptor involve activation of elements that are both dependent on and independent of protein kinase C activation. Neoplastic transformation of wild-type WB rat liver epithelial cells by exposure to N-methyl-N'-nitro-N-nitrosoguanidine is associated with progressive alterations in the responses of affected cells to binding of EGF to EGF receptors, including heightened cell proliferation and the expression of several other phenotypic properties. Tumorigenic rat liver epithelial cells acquire the ability to express transforming growth factor-alpha (TGF-alpha), and to secrete this growth factor in a regulated and then unregulated manner. TGF-alpha expression, together with the presence of abundant EGF receptors, provides affected cells with an autocrine growth cycle. The ability of transformed WB rat liver epithelial cells to produce tumors cosegregates clonally with TGF-alpha expression and with heightened expression of c-myc, c-Ha-ras and c-Ki-ras proto-oncogenes.
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PMID:Sequential changes in epidermal growth factor receptor/ligand function in cultured rat liver epithelial cells transformed chemically in vitro. 218 76


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