Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function of the Xenopus c-mos proto-oncogene product (Mos(xe)) has been investigated during oocyte maturation. Experiments with a new antibody able to immunoblot Mos(xe) demonstrated the time course of MAP kinase (MAP K) activation in oocytes paralleled Mos(xe) accumulation, and in activated eggs the deactivation of MAP K paralleled the degradation of Mos(xe). Ablation of Mos synthesis by microinjection of antisense oligodeoxynucleotides abolished activation of MAP K by progesterone, but microinjection of GST-Mos fully restored both MAP K activation and germinal vesicle breakdown (GVBD). The Mos(xe) level at metaphase of Meiosis I (MI) was 2 - 3-fold less than that at metaphase of Meiosis II (MII), but MAP K activation was maximal at metaphase in both MI and MII. In the transition between MI and MII, both cyclin B and Mos(xe) levels rapidly declined in the presence of cycloheximide and injection of exogenous GST-Mos(xe) did not prevent degradation of either protein, although MAP K was activated. Microinjection of GST-Mos(xe) into oocytes was able to activate MAP K before GVBD and H1 kinase activation, and microinjection of constitutively-activated thiophosphorylated MAP K induced de novo synthesis of Mos(xe) before H1 kinase activation, suggesting the existence of a positive feedback loop between MAP K and Mos(xe) accumulation.
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PMID:Mos proto-oncogene function during oocyte maturation in Xenopus. 866 47

The v-Src oncoprotein induces mitogenesis and transformation of cells through multiple effects on diverse signalling pathways that are influenced by the cellular context in which v-Src is expressed. Here we have examined the effects of a temperature-sensitive (ts) v-Src on transcription of the c-fos proto-oncogene, in serum-deprived and growing Rat-1 fibroblasts. We have also considered the role of mitogen-activated protein (MAP) kinase, a known mediator of ternary complex formation at the c-fos serum response element (SRE), which results in transcriptional enhancement in response to growth factors. In cells exponentially growing in the presence of serum, activation of v-Src stimulated MAP kinase and c-fos transcription. In cells made quiescent by serum deprivation, however, v-Src did not induce a c-fos transcriptional response, nor was there stimulation of ternary complex formation, despite normal activation of MAP kinase. Thus, activation of MAP kinase and stimulation of c-fos transcription and ternary complex formation are uncoupled in the absence of serum growth factors. Stimulation of c-fos by v-Src in growing cells, however, coincided with formation of a complex with an oligonucleotide spanning the c-Sis-inducible element (SIE) upstream from the SRE, suggesting that the signal transduction and activator of transcription (STAT) family of transcription factors, which bind here, may function in response to the v-Src oncoprotein. During these studies, we also observed that addition of fresh serum growth factors to growing Rat-1 fibroblasts expressing ts v-Src at the restrictive temperature resulted in substantially impaired activation of MAP kinase. This interference with normal growth factor signalling implies that catalytically inactive Src acts in a dominant negative manner by blocking normal activation of MAP kinase, although not at the expense of c-fos transcription. Thus, serum-induced c-fos transcription can also occur in an MAP kinase-independent manner.
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PMID:Uncoupling of the pathways which link MAP kinase to c-fos transcription and AP-1 in response to growth stimuli. 873 May 15

The proto-oncogene c-fos (the cellular homolog of v-fos, Finkel-Biskis-Jenkins (FBJ) murine osteogenic sarcoma virus) encodes a major component of the activator protein-1 (AP-1) transcription factor. Serum stimulation as well as oxidizing treatments induce transitory increases in c-fos mRNA abundance. The induction of c-fos by serum stimulation is also known to decline during proliferative senesence. In this study, we examined the effects of two classes of antioxidants on the induction of c-fos in early and late passage human fetal lung fibroblasts (WI-38). N-acetyl cysteine (NAC) induces c-fos transcription in both early and late passage cells, while nordihydroguaiaretic acid (NGA) induced c-fos transcription in early passage cells but fails to stimulate it in late passage cells. Since we had previously observed an age-related decline in protein kinase C (PKC) translocation from the cytosol to the membrane, following its activation, and because PKC activation appears to be involved in the NGA induction of c-fos we examined the relative protein abundances of several PKC isoforms in early and late passage cells. Additionally, we examined the protein abundance of several members of the MAP kinase pathway which could play a role in c-fos induction by the PKC-dependent pathway. We were unable to detect PKC-beta or theta in early or late passage cells. Late passage cells contained a slightly greater abundance of PKC alpha, gamma and epsilon than cells at an early passage. No other differences in PKC isoforms or in members of the MAP kinase family were observed in early or late passage cells. These results clearly demonstrate that at least some pathways leading to c-fos induction remain intact in late passage cells. While we were unable to detect any decreases in PKC isoforms or MAP kinase proteins we cannot exclude the possibility that functional decrements accumulate in these proteins during senesence.
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PMID:Effects of cellular aging on the induction of c-fos by antioxidant treatments. 873 10

Although several oncogenes, including c-myc, ras and c-raf-1, have been implicated in cellular resistance to ionising radiation, there is less information relating oncogene expression to cis-diamminedichloroplatinum (CDDP) resistance. However, transfection of c-myc or v-H-ras and activation of protein kinase C (PKC), which contributes to the RAF-1, MAP kinase signal transduction pathway, can influence therapeutic response to CDDP. Activation of PKC increases CDDP sensitivity, whilst transfected c-myc or v-H-ras induce CDDP resistance. We have previously reported that human in vitro cell lines show different patterns of sensitivity to CDDP and 4 MeV X-irradiation. In these cells radiation sensitivity is related to high levels of expression of the C-raf-1 proto-oncogene. We thus predicted that cells sensitive to CDDP might show a different relationship to c-raf-1 expression. In addition, because cyclin D1 expression can be upregulated by the myc or ras oncogenes, we also chose to study putative relationships between cyclin D1 protein levels and intrinsic cellular sensitivity to CDDP and gamma-irradiation. We report that in the 16 human cell lines which we have studied, high cyclin D1 expression is related to CDDP resistance but has no relationship with radiation responsiveness, whereas high c-raf-1 expression, although related to radiosensitivity has no relationship with CDDP responsiveness.
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PMID:Sensitivity to cis-diamminedichloroplatinum in human cancer cells is related to expression of cyclin D1 but not c-raf-1 protein. 876 May 92

In an effort to determine the role of protein kinase C-delta (PKC-delta) in cellular transformation mediated by the sis proto-oncogene, we cotransfected expression vectors containing cDNAs that encode for c-sis with an ATP binding mutant of PKC-delta (PKC-delta K376R) or wild type PKC-delta (PKC-delta WT) into NIH3T3 cells. Our results showed that expression of PKC-delta K376R severely impaired Sis-induced focus formation, whereas cotransfection of PKC-delta WT cDNA had no effect on Sis-mediated transformation. Consistent with this result, PKC-delta K376R expression also inhibited PDGF-BB-mediated anchorage-independent colony formation. While cotransfection of a vector containing a dominant negative mutant of ras (N17 ras) cDNA potently inhibited Sis-induced transformation, the expression of PKC-delta K376R did not block transformation mediated by v-H-Ras or v-Raf. In addition, PDGF-BB-induced Raf and mitogen-activated protein kinase activation, which are known to be downstream molecules in the Ras cascade, were not affected by the expression of PKC-delta K376R, indicating that PKC-delta and Ras are segregated in mediating Sis-induced transformation. Interestingly, expression of PKC-delta K376R strongly reduced TPA responsive element (TRE) transactivation induced by PDGF stimulation, suggesting that activation of TRE-containing genes, which may be involved in Sis-mediated transformation, are negatively regulated by expression of PKC-delta K376R.
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PMID:Expression of an ATP binding mutant of PKC-delta inhibits Sis-induced transformation of NIH3T3 cells. 876 Dec 94

Both mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 function downstream of the proto-oncogene product Raf in signaling pathways that affect cell proliferation and differentiation. The isoforms were previously shown to be differentially regulated in two significant ways: (a) MAPKK1, but not MAPKK2, was phosphorylated and inactivated by the cyclin-dependent kinase p34cdc2; and (b) p21 Ras formed a ternary complex with Raf/MAPKK1 but not with Raf/MAPKK2. To further characterize the regulation and function of the two isoforms, we compared their mode of activation by v-Mos and examined the transcriptional and morphological responses that they mediate in cultured mammalian cells. v-Mos enhanced the enzymatic activity of both isoforms to the same extent, by about 600-fold. Constitutively active MAPKK2 mutants were generated by introducing the same deletion and amino acid substitutions that have been shown to activate MAPKK1, suggesting that the conformational changes that lead to their activation are analogous. These mutants potentiated transcription from a promoter containing AP1-responsive elements and induced morphological transformation when expressed in mammalian cells, matching outcomes observed with constitutively active MAPKK1. The specific activity of p42 MAPK in the transformed cells was 3-fold higher than in cells expressing wild-type MAPKK, thereby implicating p42 MAPK as a common effector in vivo, and suggesting that sustained activation of p42 MAPK may represent a critical factor that contributes to the development of the transformed state. Altogether, the results demonstrate that the two isoforms elicit similar responses in vivo despite differences in their regulation.
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PMID:Constitutively active mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 mediate similar transcriptional and morphological responses. 882 8

We examined the proliferative signal transduction by EGF in HSG-AZA 3, a subclone of HSG cell line. The treatment of cells with EGF resulted in an increase in [3H]thymidine incorporation into DNA depending upon EGF concentrations. In addition, the nuclear proto-oncogene c-fos was rapidly induced by EGF. Moreover, EGF induced transient expression of EGF receptor mRNA followed by the de novo synthesis of EGF receptor protein. On the other hand, treatment of the cells with EGF occurred phosphorylation by tyrosine kinase comprised in the EGF receptor, autophosphorylation, followed by activation of MAP kinase. These results indicate that the proliferative response to EGF is modulated by the phosphorylation cascade mediating EGF receptor-associated tyrosine kinase and MAP kinase, and transient activation of c-fos protein is implicated in the cell proliferation.
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PMID:Proliferative signal transduction by epidermal growth factor (EGF) in the human salivary gland adenocarcinoma (HSG) cell line. 882 20

Although the expression of hepatocyte growth factor (HGF) and its receptor, proto-oncogene c-met, has been demonstrated in the central nervous system (CNS), the function of HGF in the CNS was not fully understood. In the present studies, we determined the effects of HGF on neuronal development in neocortical explant and mesencephalic neurons obtained from embryonic rat brain. HGF clearly enhanced neurite outgrowth in neocortical explants. In the mesencephalic culture, the number of tyrosine hydroxylase (TH)-positive neurons was significantly higher in the HGF-treated wells and the neurites of the TH-positive neurons appear to be more developed. Moreover, the dopamine uptake into mesencephalic neurons was also enhanced by HGF treatment, indicating that HGF promotes the survival and/or maturation of mesencephalic dopaminergic neurons. In both neocortical explants and mesencephalic neurons, c-met autophosphorylation was induced by HGF and MAP kinase activation was also detected in the neocortical explant. Furthermore, Western blot analysis of the cultured CNS cells revealed that HGF was expressed mainly in microglia. These results suggest that HGF from microglia has neurotrophic activity on the CNS neurons and plays significant roles in the development of the CNS.
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PMID:Neurotrophic effect of hepatocyte growth factor on central nervous system neurons in vitro. 883 90

Unfertilized frog eggs arrest at the second meiotic metaphase, due to cytostatic activity of the c-mos proto-oncogene (CSF). MAP kinase has been proposed to mediate CSF activity in suppressing cyclin degradation. Using an in vitro assay to generate CSF activity, and recombinant CL 100 phosphatase to inactivate MAP kinase, we confirm that the c-mos proto-oncogene blocks cyclin degradation through MAP kinase activation. We further show that for MAP kinase to suppress cyclin degradation, it must be activated before cyclin B-cdc2 kinase has effectively promoted cyclin degradation. Thus MAP kinase does not inactivate, but rather prevents the cyclin degradation pathway from being turned on. Using a constitutively active mutant of Ca2+/calmodulin dependent protein kinase II, which mediates the effects of Ca2+ at fertilization, we further show that the kinase can activate cyclin degradation in the presence of both MPF and the c-mos proto-oncogene without inactivating MAP kinase.
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PMID:MAP kinase does not inactivate, but rather prevents the cyclin degradation pathway from being turned on in Xenopus egg extracts. 883 8

We have evaluated the signaling pathways activated by parathyroid hormone (PTH) in SaOS2 human osteoblastlike cells correlating with induction of the c-fos proto-oncogene. Human PTH(1-34) (hPTH[1-34]) and hPTH(1-34) Nle8,18 Tyr34 induced the expression of c-fos mRNA in quiescent SaOS2 cells in a concentration-dependent manner. N-terminal truncations of hPTH(1-34) that fail to activate protein kinase A (PKA) also abolished c-fos mRNA induction. In gel retardation assays hPTH(1-34) led to a change in the mobility of specific, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)-containing protein-DNA complexes identical to that caused by other activators of PKA. The appearance of this altered mobility complex correlated temporally with the induction of c-fos mRNA. Using a c-fos serum response element probe, a slowed protein DNA complex appeared upon serum, epidermal growth factor, and basic fibroblast growth factor treatment. This slowed complex reflects phosphorylation of the transcription factor ternary complex factor (TCF) mediated via activation of the mitogen-activated protein (MAP) kinase pathway. The MAP kinase cascade is also activated by protein kinase C (PKC), and treatment with phorbol ester led to the induced TCF shift. In contrast, PTH did not produce this shift, ruling out PTH activation of c-fos via PKC and the MAP kinase signaling cascade. Further evidence for this was the lack of effect of the highly selective PKC inhibitor CGP 41251 on c-fos induction by hPTH(1-34). The janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascade targets the v-sis-inducible element in the c-fos promoter via the induced binding of STATs. Interferon gamma rapidly induced STAT binding in SaOS2 cells, unlike PTH. Thus, PTH induction of c-fos transcription appears to occur principally through activation of PKA that then targets CREB and the c-fos calcium/cAMP response element.
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PMID:Analysis of signaling pathways used by parathyroid hormone to activate the c-fos gene in human SaOS2 osteoblast-like cells. 885 42


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