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)

c-Raf-1 is a serine/threonine-specific protein kinase which is regulated by phosphorylation. A putative c-AMP dependent protein kinase PKA phosphorylation site with the consensus sequence RRXS, Ser43, and a predominant phosphorylation site of c-Raf-1, Ser259, can be phosphorylated by PKA in vitro as shown by comparison of phosphopeptide maps of recombinant wild-type c-Raf-1 and the corresponding mutants. In vivo stimulation of the PKA pathway by treatment of A431 cells with Forskolin results in increase of phosphorylation in Ser43. Forskolin reduces the upshift of c-Raf-1 induced by EGF-treatment. It inhibits the EGF-activation of the c-Raf-1 protein kinase activity tested in vitro with a peptide substrate.
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PMID:Phosphorylation of c-Raf-1 by protein kinase A interferes with activation. 800 10

The introduction of a bacterial aminoglycoside phosphotransferase gene (neo gene) into A-431 cells was found to result in disappearance of high-affinity binding sites of the epidermal growth factor receptor (EGFR), probably by affecting the phosphorylation level of the receptors. Using A-431 cells and their neo gene-transfectants, we studied the relation between "rounding" and the high-affinity sites for EGF; and we also examined the role of protein kinase C (PKC) and A (PKA) in the EGF-induced cell rounding. Pretreatment of A-431 and their transfectant cells with 12-O-tetradecanoylphorbol 13-acetate (TPA; 100 ng/ml), an activator of PKC, for 30 min inhibited both the EGF-induced cell rounding and expression of high-affinity binding sites for EGF. However, both of these responses were recovered when cells were pretreated with TPA for 20 h, which treatment is known to result in depletion of PKC by a process called "down regulation". A similar recovery was also observed when cells were pretreated with forskolin (100 microM), an activator of PKA, for 30 min. Both cell rounding and EGFR high-affinity binding sites disappeared by activation of PKC, and reappeared by activation of PKA. These results suggest that the rounding of A-431 cells by EGF was induced via the high-affinity binding sites of EGFR.
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PMID:Involvement of high-affinity binding site for EGF receptor in formation of rounding in A-431 epidermoid carcinoma cells. 800 61

The present study was to determine whether low-density lipoprotein (LDL) and oxidized LDL (Ox-LDL) modulate the heparin binding-epidermal growth factor like growth factor (HB-EGF) gene expression in rat mesangial cells (RMC). Using Northern blot analysis, LDL and Ox-LDL stimulated the expression of RMC HB-EGF mRNA in a time- and concentration-dependent manner, and the stimulatory effect of Ox-LDL lasted longer than LDL. In addition, a protein kinase C (PKC) inhibitor-staurosporine and a PKC-depletion condition abolished both of the stimulatory activities of LDL and Ox-LDL, while H-8 (a protein kinase A inhibitor) and cAMP-antagonist (cyclic adenosine-3':5'-monophosphothioate) had little effect. Our data indicate that LDL and Ox-LDL enhance HB-EGF gene expression and both via the PKC pathway in RMC. As HB-EGF is a mitogen for RMC, our results suggest that lipoproteins may regulate RMC function by inducing HB-EGF gene expression and thus contribute to glomerular injury.
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PMID:Regulation of heparin binding-epidermal growth factor like growth factor gene expression by LDL and oxidized-LDL in rat mesangial cells. 804 11

Tumor necrosis factor-alpha (TNF) induces clustering of theca-interstitial cells (TIC) isolated from immature, hypophysectomized rats, while inhibiting luteinizing hormone (LH)-stimulated androstenedione in vitro. Stimulators of PKC, 1-oleoyl-2-acetyl-sn-glycerol (OAG, 50 and 100 microM) and phorbol-12-myristate-13-acetate (PMA, 50 nM), caused TIC clustering by 6 days in vitro. Clustering induced by these compounds resembled that induced by TNF. The protein kinase inhibitor, staurosporine at 1 and 10 nM, impaired TNF-induced TIC clustering for 6 days, as did the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperizine dihydrochloride (H-7); conversely, the protein kinase inhibitor, chelerythrine chloride (0.1, 1.0 or 10 microM), did not attenuate TNF-directed clustering. The protein kinase inhibitors did not reverse the suppression of LH-stimulated androstenedione by TNF. Inhibitors of the EGF receptor PTK, A23 (10, 50, or 100 microM) and A46 (0.1, 1.0, 10, or 50 microM), impaired TNF-induced TIC clustering, while TNF suppression of LH-directed androstenedione was unaffected. EGF-induced TIC clustering was also impaired by A46, while A23 was less effective. Both A23 and A46 blocked EGF attenuation of LH-directed androstenedione after 4 days. When challenged with TNF (1 ng/ml) or PMA (50 nM), PKC activity increased in TIC. A23 (50 microM) and A46 (10 microM) each alone blocked the TNF-associated increase in PKC activity; however, PKC activity attributable to PMA was unaffected by A46. Together, these results suggest that TNF-induced TIC clustering involves activation of PTK which directs subsequent increases in PKC activity; however, mechanisms by which TNF inhibits LH-stimulated steroidogenesis remains elusive.
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PMID:Involvement of protein kinase C and protein tyrosine kinase pathways in tumor necrosis factor-alpha-induced clustering of ovarian theca-interstitial cells. 814 4

Lactoferrin is present in a variety of tissues and biological fluids; however, the amount differs significantly due to differential expressions. We have previously demonstrated that the mouse lactoferrin gene is regulated by estrogen through an estrogen-response DNA element located at -349, upstream from the transcription start site (+1). In this report, we characterized by deletion and mutation analyses a cluster of mitogen-response elements located between -80 and -40 of the mouse lactoferrin promoter. We demonstrated that the chimeric chloramphenicol acetyltransferase reporter constructs (the -103 to +1 sequence of the mouse lactoferrin gene) containing the mitogen-response unit of the lactoferrin gene were stimulated by cAMP, forskolin, 12-O-tetradecanoylphorbol-13-acetate, and epidermal growth factor/recombinant transforming growth factor-alpha (EGF/TGF-alpha) in a time- and dose-dependent manner. The sequence at position -52 to -40 (mLF-CRE) of the gene conferred transcriptional activation in the presence of forskolin, cyclic AMP, and 12-O-tetradecanoylphorbol-13-acetate in transiently transfected human endometrium carcinoma RL95-2 cells, whereas the region at -80 to -60 responded to EGF/TGF-alpha stimulation. Overexpression of the catalytic unit of protein kinase C or protein kinase A in the RL95-2 cells elevated the chloramphenicol acetyl-transferase activity of the reporter construct 5-6-fold. The mobility shift assay suggested that AP1 and CREB or related proteins participated in complex formation with the mLF-CRE, whereas different proteins bound to the EGF/TGF-alpha-response element.
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PMID:Characterization of a mitogen-response unit in the mouse lactoferrin gene promoter. 817 15

The signal transduction of TSH in invasion and growth of FTC 133, a human follicular thyroid cancer cell line, was investigated. TSH (0.01-1 mIU/ml) stimulated invasion of FTC 133 by 21% and growth by 20% of basal. Cyclic AMP-stimulators and inhibitors had no effect at any concentration. The PKC-agonist TPA enhanced invasion and growth by 15%, whereas staurosporine, a PKC-antagonist, inhibited them by 32% and 60%, respectively. The latter also reversed TSH stimulation. EGF enhanced invasion (42%) and growth of FTC 133 (25%). Staurosporine did not reverse EGF stimulation. The tyrosine kinase antagonist genistein reversed EGF, but not TSH stimulation. Pertussis toxin inhibited invasion (18%) and growth (22%). Cholera toxin was less inhibitive. We demonstrated for the first time, that TSH stimulates invasion and growth of human thyroid cancer cells in vitro by PKC- rather than PKA-stimulation.
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PMID:Thyrotropin stimulates invasion and growth of follicular thyroid cancer cells via PKC- rather than PKA-activation. 821 54

In fibroblasts, stimulation of receptor tyrosine kinases results in the activation of the extracellular signal-regulated kinase 2 (ERK2). The major signalling pathway employed by these receptors involves the activation of p21ras and raf-1 kinase. Here we show that in NIH3T3 and rat-1 fibroblasts, elevation of the intracellular cAMP level results in the inhibition of ERK2 activation induced by PDGF, EGF and insulin treatment. Analysis of various signalling intermediates shows that cAMP interferes at a site downstream of p21ras, but upstream of raf-1 kinase. Inhibition by cAMP depends on both the cAMP concentration and the absolute amount of p21ras molecules bound to GTP, suggesting a mechanism of competitive inhibition. Also TPA-induced, p21ras-independent, activation of raf-1 kinase and ERK2 is inhibited by cAMP. We have used the inhibitory effect of cAMP to investigate whether phosphorylation of mSos, a p21ras nucleotide exchange factor, is dependent on the activity of the raf-1 kinase/ERK2 pathway. We found that phosphorylation of mSos, as monitored by a mobility shift, is delayed with respect to p21ras and ERK2 activation and is inhibited by cAMP in a similar cell type- and concentration-dependent manner as the inactivation of ERK2. These results provide evidence for a model of p21ras-directed signalling towards ERK2 that feeds back on mSos by regulating its phosphorylation status and that can be negatively modulated by protein kinase A and positively modulated by protein kinase C action.
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PMID:cAMP antagonizes p21ras-directed activation of extracellular signal-regulated kinase 2 and phosphorylation of mSos nucleotide exchange factor. 822 35

Human cytotrophoblasts in culture aggregate and fuse to form syncytiotrophoblasts. This process is associated with an increase in epidermal growth factor receptor (EGFR) expression [Alsat et al.: J Cell Physiol 154:122-128, 1993]. Recent studies have demonstrated the presence of parathyroid hormone-related protein (PTHrP) in the human uterus and placenta. This led us to study the effect of PTH (1-34) and PTHrP (1-34) on the expression of EGFR during this differentiation process. Both peptides induced a concentration-dependent increase in EGF binding, with a maximal effect at the physiological concentration of 1 nM. EGFR protein level assessed by cross-linking and immunoblotting and EGFR biological activity assessed by measuring its EGF-induced autophosphorylation were increased 2- and 2.5-fold, respectively, when cells were treated for 24 h with 0.1 microM PTHrP or PTH compared to control cells. This effect was time-dependent with a maximum at 3 h of treatment. This treatment also increased trophoblast cell EGFR mRNA levels, suggesting transcriptional regulation of the EGFR. To ascertain whether activation of protein kinase C (PKC) or protein kinase A (PKA) is involved in this PTH effect, we determined EGFR protein level and EGFR autophosphorylation after exposure of cells to PKA inhibitor and PKC inhibitor, alone or together with the peptide. The presence of a PKC inhibitor blocked a further increase in EGFR number by PTH, while PKA inhibitor had no effect. These results show that PTH and PTHrP increase the synthesis of EGF receptors which are strongly expressed in syncytiotrophoblasts and suggested that these peptides might be involved in human placental development.
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PMID:Increase in epidermal growth factor receptor and its mRNA levels by parathyroid hormone (1-34) and parathyroid hormone-related protein (1-34) during differentiation of human trophoblast cells in culture. 822 81

Ovariectomized mice were either sham operated or sialoadenectomized and injected daily for 18 days with saline, estradiol + progesterone, cholera toxin or estradiol + progesterone+cholera toxin. Mammary development score and DNA were increased by estradiol + progesterone, but not by cholera toxin alone. In combination with estradiol + progesterone, cholera toxin increased mammary development score and mammary DNA. Sialoadenectomy reduced the ability of estradiol, progesterone and cholera toxin to induce mammary development. In other experiments, mice were primed with estradiol + progesterone for 10 days, and mammary tissue removed for in vitro culture with various combinations of insulin, aldosterone, cholera toxin and epidermal growth factor. In combination with insulin and aldosterone, cholera toxin increased mammary development in vitro. Sialoadenectomy reduced the ability of cholera toxin to induce mammary development in vitro. The effect of sialoadenectomy on mammary development was alleviated by adding epidermal growth factor to culture medium. Biochemical studies indicated that sialoadenectomy reduced the ability of estrogen and progesterone to induce cyclic AMP dependent protein kinase levels in mammary tissue, and also the ability of cholera toxin to induce accumulation of cyclic AMP in tissues. These effects of sialoadenectomy were reversed by addition of EGF to culture media.
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PMID:Epidermal growth factor modulates cholera toxin induced mammary gland development. 830 42

The amphibian tetradecapeptide bombesin as well as the bombesin-related mammalian peptides are potent mitogens for Swiss 3T3 cells. Other sole mitogens for Swiss 3T3 cells, such as PDGF and FGF, invariably signal through a tyrosine kinase receptor. The bombesin receptor has been cloned from Swiss 3T3 fibroblasts and was shown to be a member of the family of G-protein-linked neuropeptide receptors, whose sequence does not reveal a protein kinase domain. Upon binding to its receptor, bombesin evokes a complex cascade of early biochemical events including inositol 1,4,5-trisphosphate-induced mobilization of intracellular Ca2+, Na+ and K+ fluxes, PK-C activation, transmodulation of the EGF-receptor, accumulation and expression of the proto-oncogenes c-fos and c-myc and cAMP production. The intermediates in this signaling pathway are still largely unknown. Since many hormones and neuropeptides that signal through similar receptors with seven membrane spanning domains are by themselves not mitogenic for Swiss 3T3 fibroblasts, we suggest that bombesin acts through a rather special signaling pathway. Although its receptor does not feature a cytoplasmic tyrosine kinase domain, bombesin rapidly stimulates the tyrosine phosphorylation of multiple protein substrates, which are however quite distinct from the usual targets of tyrosine kinase receptors. Yet, a similar cascade of Ser/Thr protein kinases is activated downstream of these differentiating tyrosine kinase events, since, like EGF or insulin, bombesin rapidly stimulates the activity of two MBP kinases as well as several S6 peptide kinases. The present report furthermore implicates CK-2 in the early signal transduction pathway of this mitogen, and it is postulated that the activation of CK-2 may be an intrinsic property of "sole mitogens" like bombesin, as it may be a compulsory event leading to cell division. In that respect, CK-2 may also be the point of integration of multiple signaling pathways, initiated by several different growth factors which by their synergistic actions make cell proliferation possible.
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PMID:Early responses in mitogenic signaling, bombesin induced protein phosphorylations in Swiss 3T3 cells. 839 34


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