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)

Our previous work on protein kinase C (PKC) and colon cancer has shown altered levels of PKC activity in human colon tumors, as well as activation of PKC by colon tumor promoters such as bile acids. To understand further the role of PKC in colon carcinogenesis, we analyzed the expression of phorbin, a gene induced by PKC activation, in a series of different stages of human colon tumors. As shown by northern blot analyses of poly (A)+ RNA, higher levels of phorbin RNA were seen in 26 colon tumor samples than in their adjacent normal colonic mucosa. There also appeared to be a correlation between the abundance of phorbin RNA in the tumors and the extent of invasion (tumor-to-normal tissue phorbin RNA ratio = 4.2, 8.0, and 11.9 for Dukes' A, B, and C, respectively). Phorbin RNA was also abundant in a human colon cancer line (HT29). We also examined the expression of other mitogen-responsive genes (c-myc, ODC, and beta-actin) in a set of 19 colon tumor samples. All tumors displayed significant (mean 3.8-fold) increases in the level of c-myc RNA compared with their adjacent normal colonic mucosa. About 47% and 16% of these tumor samples also showed increased levels of ODC (mean 3.1-fold) and beta-actin (mean 1.6-fold) RNA, respectively. The increased levels of c-myc, ODC, and beta-actin RNA did not correlate with the extent of tumor invasion. Taken together, these results demonstrate that human colon tumors usually display increased levels of both phorbin and c-myc RNAs. The marked increases in phorbin RNA suggest that this could serve as a useful biomarker in studies on human colon cancer.
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PMID:Increased levels of phorbin, c-myc, and ornithine decarboxylase RNAs in human colon cancer. 169 76

HLA class I antigens seem to be involved in the proliferative response of PHA-activated human T-lymphocytes. We have previously reported that the treatment of PHA-activated peripheral blood mononuclear cells (PBMC) with an anti-HLA class I monoclonal antibody, 01.65, (i) inhibits the tritiated thymidine incorporation, (ii) inactivates cytosolic protein kinase C (PKC) and (iii) causes an increase in the duration of the cell cycle. Northern Blot kinetic analysis of c-fos, c-myc, cdc2, IL-2R, c-myb, ODC, TK and H3, from 10 minutes to 120 hours, was performed in MAb 01.65 treated cultures. We found that the expression of four genes (c-myc, IL-2R, cdc2 and TK) was depressed 24 hours after PHA stimulation.
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PMID:Molecular analysis of cell cycle-related gene expression in anti-HLA class I monoclonal antibody (01.65) treated PHA-activated human T-lymphocytes. 177 40

The trophic effects of prolactin (PRL) in rat liver have been linked to activation of protein kinase C (PKC). Since alterations in PKC activity imply its activation by 1,2-diacylglycerol (DAG), we tested whether PRL treatment stimulated DAG generation coupled to induction of a growth response in primary hepatocytes. Addition of PRL to hepatocyte cultures significantly increased [3H]-glycerol incorporation into DAG within 5 minutes which was followed by a loss of cytosolic PKC activity by 10 minutes. Prolactin also significantly enhanced radiolabel incorporation into triacylglycerol and phospholipids within 10 minutes and induced ODC activity at 6 hours. Therefore, prolactin-stimulated alterations in PKC activity are preceded by enhanced DAG generation. Moreover, these events appear to be coupled to PRL-stimulated entry of hepatocytes into cell cycle.
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PMID:Prolactin-stimulated ornithine decarboxylase induction in rat hepatocytes: coupling to diacylglycerol generation and protein kinase C. 199 81

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulates a rapid increase in ornithine decarboxylase (EC 4.1.1.17; ODC) activity in target cells. Here we demonstrate that this process involves a rapid accumulation of ODC mRNA, which is maximal 3 h after treatment (three- to eightfold greater than control cells) and decays to control levels within 18 h. Stimulation of ODC mRNA by TPA is blocked by phorbol dibutyrate down-regulation of protein kinase C (PKC). ODC mRNA was also induced by the PKC activators, phospholipase C and 1-oleoyl-2-acetyl-rac-glycerol, and blocked by kinase inhibitors (trifluoroperazine, H7, and palmitoyl-L-carnitine), consistent with a requirement for PKC activation in the induction mechanism. However, the non-PKC-specific protein kinase inhibitor HA1004 also suppressed expression of ODC mRNA in response to TPA, under conditions where it did not inhibit PKC, suggesting that additional kinases may be involved in the intracellular signalling process. The stability of the ODC mRNA (control value = 6.2 +/- 1.6 h) is not significantly changed by either TPA (5.7 +/- 0.8 h) or by cycloheximide (6.0 h). These results are inconsistent with any contribution from altered mRNA half-life towards the accumulation of ODC mRNA following treatment with phorbol ester tumor promoters.
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PMID:Involvement of protein kinase C in the regulation of ornithine decarboxylase mRNA by phorbol esters in rat hepatoma cells. 201 52

We have used a previously described retroviral expression vector pMV7-PKC beta 1 to develop derivatives of two rat liver epithelial cell lines, K16 and K22, that stably express about tenfold-higher PKC activity than control cells. Despite these high levels of PKC, these cells did not exhibit gross morphologic changes, anchorage-independent growth, or tumorigenicity. K16PKC-4 and K22PKC-2, two lines with the highest PKC enzyme activity, were studied further in terms of several responses to the phorbol ester tumor promoter TPA. When treated with 100 ng/ml of TPA, the control K16MV7 and K22MV7 cells displayed a slight change in morphology, whereas the K16PKC-4 and K22PKC-2 cells displayed a marked change in morphology. Northern blot analyses demonstrated that TPA induced increased levels of fos, myc, phorbin, and ODC RNAs in control K16MV7 and K22MV7 cells, with maximum induction occurring at about 0.5, 1, 8, and 8 h, respectively. In K16PKC-4 and K22PKC-2 cells, TPA induction of phorbin and ODC RNAs was markedly enhanced, but this was not the case for myc and fos RNAs. In addition, the levels of myc RNA were constitutively higher in both K16PKC-4 and K22PKC-2 cells than in the control cells. Taken together, these results provide direct evidence that PKC plays a critical role in modulating the expression of myc, phorbin, and ODC RNAs. On the other hand, overexpression of PKC beta 1 is not itself sufficient to cause cell transformation.
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PMID:Phenotypic effects of overexpression of PKC beta 1 in rat liver epithelial cells. 253 31

Induction of ornithine decarboxylase (ODC, E.C. 4.1.1.17) activity by parathyroid hormone (PTH) in cultured fetal rat osteoblasts was studied. PTH induced ODC activity and stimulated cAMP production in a dose-dependent manner, the ED50 for cAMP being five times as high as that for ODC. Induction of ODC activity by PTH was partly inhibited by actinomycin D and cycloheximide, with 40 and 55% inhibition, respectively. PTH increased the intracellular ionized calcium concentration ([Ca2+]i), which was absent in a Ca2+-free medium. Blocking calcium influx, lowering the extracellular calcium concentration, and adding trifluoperazine inhibited both induction of ODC activity and stimulation of cAMP production by PTH. A23187 (100 nM and 1 microM), combined with a low dose of PTH (4 nM), resulted in a synergistic induction of ODC activity and an inhibition of cAMP production. A23187 inhibited induction of ODC activity as well as stimulation of cAMP production by the dose of PTH (20 nM) maximally effective in inducing ODC activity. Forskolin together with this maximal dose of PTH resulted in an additive effect on ODC activity and a synergistic stimulation of cAMP production. The current results show similarities and differences with respect to results obtained with osteoblasts from other species and osteoblast cell lines. The present data indicate that (1) PTH stimulates ODC activity and this is partly due to new enzyme synthesis; (2) calcium is involved in induction of ODC activity and stimulation of cAMP production by PTH; furthermore, it is suggestive that calmodulin and/or protein kinase C are involved; and (3) stimulation of cAMP production by PTH depends on an optimal intracellular calcium concentration range.
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PMID:Parathyroid hormone-induced ornithine decarboxylase activity in fetal rat osteoblasts. 255 85

The polypeptide hormones governing the proliferation and differentiation of the mature immune system and hematopoiesis are collectively referred to as lymphokines. We have examined a number of biochemical and molecular events stimulated by several unique lymphokines which exhibit proliferative activity on lymphoid and myeloid cell lines. Interleukin-2 (IL-2) and several members of the colony-stimulating factors (IL-3, G-CSF, and GM-CSF) stimulate similar patterns of cellular phosphorylation including the prominent phosphorylation of a 68-kDa substrate present in numerous distinct lineage cell lines. The 68-kDa substrate is phosphorylated by protein kinase C on threonine residues and is primarily cytosolic. Another kinase system activated by either physiological ligand or synthetic diacylglycerol phosphorylated the 40S ribosomal protein in a dose-dependent manner. The increased phosphorylation of S6 protein was associated with enhanced chain elongation in vitro. The kinase responsible for the in situ phosphorylation, however, was not protein kinase-C (PK-C) but another physicochemically distinct Mg2+-dependent enzyme (termed S6 kinase). These studies suggested that, although PK-C was activated by diacylglycerol, another kinase, S6 kinase, was the effector enzyme involved in the phosphorylation of the 40S protein. IL-2 and all other CSFs tested stimulated the transcription of the nuclear protooncogenes c-fos, c-myc, and c-myb. In addition, ornithine decarboxylase mRNA accumulation was also stimulated. Phorbol esters also stimulated similar gene expression; however, cyclic AMP analog inhibited phorbol ester or ligand-induced c-myc expression and ODC mRNA accumulation. Cyclic AMP agonists are antiproliferative to all the growth factors tested. We have constructed complementary oligonucleotides, "antisense", against c-fos, c-myc, and other structural genes induced by the growth factors. Such antisense oligomers were capable of selectively deleting protein expression of the respective gene products and inhibited the biological action of the growth factors.
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PMID:The molecular basis of immune cytokine action. 265 49

Ten new tumor promoters which are structurally different from TPA but of similar biological activity were found. Based on their binding to the phorbol ester receptors of cell membranes, these new tumor promoters were classified as TPA-type tumor promoters, teleocidin and aplysiatoxin, which like TPA, activated protein kinase C in vitro, whereas two non-TPA-type tumor promoters, palytoxin and thapsigargin did not induce ODC activity in mouse skin, adhesion of HL-60 cells or activation of protein kinase C, but did show tumor-promoting activity in a two-stage carcinogenesis experiment. Although these two types of tumor promoter exert their tumor-promoting activities through different pathways, production of prostaglandin E2 by rat macrophages was induced by both the TPA-type and non-TPA-type promoters. Therefore, stimulation of arachidonic acid metabolism is suggested to be one of the important biological activities for tumor promotion.
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PMID:[The actions of TPA-type as well as non-TPA type tumor promoters and their mechanism(s) in tumor promotion]. 287 Jun 84

ODC, the first enzyme in mammalian polyamine biosynthesis, is rapidly induced in response to a wide variety of growth stimuli. However, there is no single mechanism which may explain the rapid turnover of ODC activity. ODC activity has been shown to be regulated at the level of synthesis and degradation, and also by post-translational modifications and an interaction with macromolecules. Our results indicate that TPA-induced ODC activity is regulated at the transcriptional level. An initial signal in ODC induction by TPA is not clear. We have suggested that TPA-increased accumulation of epidermal prostaglandins is required, but not sufficient, for ODC induction by TPA. Others have suggested the role of lipoxygenase product(s) in ODC induction. The role of the microtubule-containing system in regulation of ODC induction has been shown. The involvement of cyclic nucleotides in ODC induction by TPA is controversial. Also, generation of free radicals appears to be involved in ODC induction by TPA. Data summarized in this chapter indicate that activation of PKC may be an initial step in ODC induction by TPA.
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PMID:Mechanisms involved in ornithine decarboxylase induction by 12-O-tetradecanoylphorbol-13-acetate, a potent mouse skin tumor promoter and an activator of protein kinase C. 307 26

Phospholipase A2 inhibitors and lipoxygenase inhibitors markedly suppressed mouse skin ODC (ornithine decarboxylase) induction and promotion of papilloma by TPA. The inhibitory potency was related to the inhibition of epidermal 12-lipoxygenase. Lipoxygenase inhibitors, such as AA 861 and tetrahydrochalcone were lacking in the inhibitory action on protein kinase C. Moreover, palmitoylcarnitin, a protein kinase C inhibitor, inhibited TPA-induced differention of HL 60 cells and TPA-induced epidermal ODC induction and tumor promotion in mouse skin. Intraperitoneal injection of TPA also induced ODC in liver, kidney and spleen, but not in the skin of mice. In isolated mouse epidermal cells, TPA and diacylglycerol induced ODC. The induction of ODC was inhibited by phospholipase A2 inhibitors, lipoxygenase inhibitors, anticalmodulines, Ca++ entry blockers and Ca++ antagonists. These results indicate that intracellular Ca++ is involved in TPA induction of ODC.
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PMID:[Factors controlling tumor promotion induced by TPA]. 308 83


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