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)

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.
 ...
PMID:[Factors controlling tumor promotion induced by TPA]. 308 83

The tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with calcium ionophores has been shown to bypass the requisite antigen- or lectin-induced signal for lymphocyte mitogenesis. This suggests that protein kinase C activation and calcium mobilization may be early events required for lymphocyte proliferation. Therefore, the relationship(s) of protein kinase C activation and calcium mobilization to ornithine decarboxylase induction and cellular proliferation were examined in a rat node lymphoma cell line (Nb2) which is dependent upon prolactin (PRL) for mitogenesis. TPA enhanced PRL-stimulated Nb2 node lymphoma cell ornithine decarboxylase induction and [3H]thymidine incorporation. Addition of a calcium ionophore (A23187) to cultures containing TPA plus PRL increased ornithine decarboxylase above PRL alone or PRL plus TPA but inhibited proliferation compared to the PRL plus TPA regimen. Exposure of cells to TPA or TPA plus A23187 increased [3H]thymidine incorporation in a similar manner to that demonstrated for low-dose PRL. However, optimal concentrations were only 20-25% as effective as mitogens as was optimal PRL. Protein kinase C and calmodulin antagonists inhibited PRL-stimulated ornithine decarboxylase induction and proliferation. Ca2+ chelation or cation channel antagonism inhibited both PRL-stimulated responses. The cyclic AMP analogue, 8Br-cAMP, inhibited PRL-stimulated ornithine decarboxylase activity as well as cellular proliferation processes assessed by [3H]thymidine incorporation. Finally, tumor-promoting phorbol esters inhibited 125I-rPRL binding. These data strongly suggest that protein kinase C activation and calcium mobilization are requisite events for PRL-stimulated ornithine decarboxylase induction and cellular proliferation in Nb2 node lymphoma cells. An additional component that is linked to alterations in K+ channeling is also implicated. These data support a role for protein kinase C in PRL-coupled mitogenesis. However, other critical Ca2+ and/or ion-induced events are also required.
 ...
PMID:Prolactin stimulation of ornithine decarboxylase and mitogenesis in Nb2 node lymphoma cells: the role of protein kinase C and calcium mobilization. 309 4

Both 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) and 3,4,2',4'-tetrahydroxychalcone inhibited 12-lipoxygenase of mouse epidermis. The IC50 of AA861 and 3,4,2',4'-tetrahydroxychalcone for epidermal 12-lipoxygenase were 1.9 and 0.2 microM, respectively. These agents showed very weak inhibitory actions on epidermal cyclooxygenase, with the potency of inhibition for cyclooxygenase less than 1/50 of that for lipoxygenase. Induction of epidermal ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate (TPA; 10 nmol/mouse) was potently inhibited by these agents in a dose-dependent manner (1-30 mumol/mouse). TPA (5 nmol/mouse)-induced skin tumor formation was also strongly suppressed by these agents (15 mumol/mouse). Both AA861 and 3,4,2',4'-tetrahydroxychalcone failed to inhibit partially purified epidermal protein kinase C activity. These results support the proposed involvement of lipoxygenase product(s) of arachidonic acid in TPA-induced skin tumor promotion.
 ...
PMID:Inhibition of 12-O-tetradecanoylphorbol-13-acetate-mediated epidermal ornithine decarboxylase induction and skin tumor promotion by new lipoxygenase inhibitors lacking protein kinase C inhibitory effects. 309 75

Prolactin (PRL)-stimulated ornithine decarboxylase (ODC) activity and subsequent proliferation are inhibited by the cyclopeptides cyclosporine (CsA) and didemnin B (DB) in Nb 2 node lymphoma cells. Similar concentrations of these agents also inhibit 125I-PRL binding, suggesting that their inhibitory effects on these PRL-dependent physiologic responses are mediated at least in part at the level of PRL receptor interactions. The phorbol ester TPA stimulated ODC activity and [3H]thymidine incorporation to 54% and 31% that of a near-optimal mitogenic concentration of PRL (10 ng/ml), suggesting that mitogenesis in these cells is coupled to some degree to the activation of protein kinase C (PKC). The calcium ionophore A23187 increased ODC activity only slightly and actually decreased [3H]thymidine incorporation to a value below the "cells only" controls. The addition of TPA plus A23187 did not further enhance the effects of TPA to elevate ODC activity and [3H]thymidine incorporation. However, A23187 significantly elevated PRL-stimulated ODC activity with a subsequent inhibition of [3H]thymidine incorporation, suggesting a block of entry into S phase. Both cyclopeptides decreased the elevation of ODC activity in G1 phase of cell cycle in response to PRL, suggestive of a site of action for these agents in early G1, a conclusion compatible with their ability to inhibit PRL binding to these cells. Addition of CsA or DB 2 hr after PRL had no effect on PRL-stimulated ODC activity detectable at 6 hr, but addition of either as late as 6 hr still affected the extent of mitogenesis. This is in line with the requirement for PRL to be present in the culture medium for a minimum of 3 to 6 hr to invoke a maximal effect on mitogenesis. Addition of either cyclopeptide after the cells were in S phase had no effect on the extent of [3H]thymidine incorporation. An inhibitor of the cyclooxygenase pathway (indomethacin) enhanced both PRL-stimulated ODC activity and proliferation, whereas inhibition of the lipoxygenase pathway by NDGA attenuated only proliferation, suggesting that in Nb 2 cells, products of the lipoxygenase pathway may contribute to the mechanism of PRL-stimulated mitogenesis. Because Nb 2 lymphoma cells were derived from estrogenized rats, estrogen was tested as a mitogen. By itself it was not mitogenic, but in conjunction with PRL, estradiol-17 beta elevated the ODC response and inhibited proliferation. Inhibitors of PKC known to have minimal effects on RNA synthesis, quercetin and gossypol, totally inhibited both the elevations of ODC activity and [3H]thymidine incorporation in response to PRL in Nb 2 lymphoma cells.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Prolactin-dependent mitogenesis in Nb 2 node lymphoma cells: effects of immunosuppressive cyclopeptides. 309 47

(-)-Indolactam-V, which has the partial structure of teleocidins A and B, and has tumor-promoting activity, is a good model for use in studies on the relation between structure and tumor-promoting activity, whereas (+)-indolactam-V has no tumor-promoting activity. In this work, five racemic indolactams differing only in their alkyl group at C-12 of (-)-indolactam-V were synthesized and tested for biological and biochemical activities related to tumor promotion. The activities tested were inductions of ornithine decarboxylase in mouse skin and human promyelocytic leukemia (HL-60) cell adhesion, inhibition of specific [3H]12-O-tetradecanoyl-phorbol-13-acetate binding to a mouse particulate fraction and activation of protein kinase C in vitro. The results showed that (+/-)-indolactam-L and (+/-)-indolactam-F had almost the same activities as (+/-)-indolactam-V, suggesting that (-)-indolactam-L and (-)-indolactam-F are new tumor promoters with as high potency as (-)-indolactam-V. (+/-)-Indolactam-t-L, which has a highly lipophilic group at C-12 of (-)-indolactam-V, showed the highest activities in the above tests. (-)-Indolactam-t-L might have stronger tumor-promoting activity than (-)-indolactam-V. Furthermore, the results with (-)-indolactam-t-L indicated the possibility of designing new tumor promoters with stronger activity than teleocidin.
 ...
PMID:Synthetic analogues (indolactams) of (-)-indolactam-V are new congeners of the teleocidin class of tumor promoters. 311 73

Okadaic acid is a polyether compound of a C38 fatty acid, isolated from a black sponge, Halichondria okadai. Previous studies showed that okadaic acid is a skin irritant and induces ornithine decarboxylase (OrnDCase; 3-hydroxyl-L-glutamate 1-carboxy-lyase, EC 4.1.1.17) in mouse skin 4 hr after its application to the skin. This induction was strongly inhibited by pretreatment of the skin with 13-cis-retinoic acid. A two-stage carcinogenesis experiment in mouse skin initiated by a single application of 100 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA) and followed by application of 10 micrograms of okadaic acid twice a week revealed that okadaic acid is a potent additional tumor promoter: tumors developed in 93% of the mice treated with DMBA and okadaic acid by week 16. In contrast, tumors were found in only one mouse each in the groups treated with DMBA alone or okadaic acid alone. An average of 2.6 tumors per mouse was found in week 30 in the group treated with DMBA and okadaic acid. Unlike phorbol 12-tetradecanoate 13-acetate (TPA), teleocidin, and aplysiatoxin, okadaic acid did not inhibit the specific binding of [3H]TPA to a mouse skin particulate fraction when added up to 100 microM or activate calcium-activated, phospholipid-dependent protein kinase (protein kinase C) in vitro when added up to 1.2 microM. Therefore, the actions of okadaic acid and phorbol ester may be mediated in different ways. These results show that okadaic acid is a non-TPA-type tumor promoter in mouse skin carcinogenesis.
 ...
PMID:Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter. 312 94

Endogenous diacylglycerol, as produced during ligand-stimulated hydrolysis of phosphatidylinositol, is a physiological activator of protein kinase C, a receptor for the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Diacylglycerol mimics many effects of phorbol ester TPA, but it is not known whether diacylglycerol is a mouse skin tumor promoter. The present studies determined the mouse skin tumor-promoting activity of L-alpha-dioctanoylglycerol (DG), a membrane-permeable diacylglycerol derivative. In two independent experiments with female SENCAR mice, DG at a 2 mumol dose, when applied twice weekly to the initiated mouse skin, failed to promote mouse skin tumor formation. Similarly, DG lacked Stage I tumor-promoting activity; twice weekly applications of DG for 2 wk to the initiated mouse skin followed by twice weekly applications of mezerein (3.3 nmol) for as long as 27 wk elicited only a few papillomas per mouse. DG was found to be a potent Stage II mouse skin tumor promoter. In a typical two-stage tumor promotion experiment, SENCAR mice were initiated by application of 20 nmol of DMBA to their shaved backs. Two wk after initiation, 3.3 nmol of TPA were applied twice weekly for 2 wk (Stage I), and then 2 mumol of DG or 3.3 nmol of mezerein were applied to the skin twice weekly for the entire duration of the experiment (Stage II). Stage II tumor promotion with mezerein and DG resulted in 13.33 +/- 0.88 and 11.13 +/- 1.25 papillomas per mouse, respectively, at 19 wk and the carcinoma incidence, 43% and 33%, respectively, at 27 wk of promotion. The tumor-promoting activity of DG was compared with the parent alcohol glycerol, and it was found that glycerol, at a dose as high as 11 mumol, was not a complete, Stage I or Stage II mouse skin tumor promoter. Both TPA and DG, when applied to mouse skin, induced epidermal ornithine decarboxylase activity. Both TPA and DG activate protein kinase C, but the results presented indicate that TPA and DG differ in their tumor-promoting properties. DG, like mezerein, is a Stage II mouse skin tumor promoter.
 ...
PMID:The protein kinase C activator L-alpha-dioctanoylglycerol: a potent stage II mouse skin tumor promoter. 312 39

Teleocidin, isolated from mycelia of Streptomyces mediocidicus is a mixture of two teleocidin A isomers with molecular weights of 437 (A-1 and A-2) and four teleocidin B isomers with molecular weights of 451 (B-1, B-2, B-3, and B-4). Previously we found that each purified isomer of teleocidins A and B had approximately the same activity as teleocidin in an irritant test on mouse ear, in inductions of ornithine decarboxylase in mouse skin and adhesion of human promyelocytic leukemia (HL-60) cells, and in inhibition of the specific binding of [3H]-12-O-tetradecanoylphorbol-13-acetate to a mouse skin particulate fraction. This paper reports the strong activation of protein kinase C in vitro by each isomer of teleocidins A and B at a concentration of 1 microgram/ml. Detailed studies on the potent tumor promoting activities of the two teleocidin A isomers and four teleocidin B isomers in a two-stage carcinogenesis experiment on mouse skin are also reported, including histological findings on the tumors. Treatment of mice with 100 micrograms of 7,12-dimethylbenz(a)anthracene and then 2.5 micrograms of any one of the six isomers of teleocidins A and B twice a week induced tumors in 80.0 to 91.7% of the mice with 2.8 to 5.2 tumors/mouse in week 30. Scarcely any tumors developed in groups treated with 7,12-dimethylbenz(a)anthracene or any one of the isomers of teleocidins A or B alone. The percentages of incidences of mice bearing papillomas and carcinomas in the six groups treated with 7,12-dimethylbenz(a)anthracene plus one isomer of teleocidins A or B were 90.9 to 98.3% and 1.7 to 9.1%, respectively. These results indicate that all of the isomers of teleocidins A and B have potent tumor promoting activity on mouse skin, irrespective of the structural differences between teleocidins A-1 and A-2, and among the four isomers of teleocidin B. The structure-activity relationship of teleocidins A and B is discussed on the basis of our recent results. Based on the structures of related compounds, we propose a revised numbering system for compounds of the teleocidin class.
 ...
PMID:Similar, potent tumor-promoting activity of all isomers of teleocidins A and B in a two-stage carcinogenesis experiment on the skin of CD-1 mice. 313 23

Some, but not all, studies have suggested that high-fat diets promote colon carcinogenesis, possibly by stimulating the proliferative activity of colonic epithelium. Both the increase in colonic excretion of bile salts and of fatty acids that occur with an increase in fat ingestion have been implicated as stimuli of epithelial proliferative activity. In this study, we examined the role of activation of protein kinase C in fatty acid-induced stimulation of colonic epithelial proliferation in the rat. Intracolonic instillation of arachidonate, linoleate, or oleate at concentrations that did not induce surface cell injury or loss increased colonic mucosal ornithine decarboxylase activity and stimulated incorporation of [3H]thymidine into mucosal deoxyribonucleic acid. The saturated fatty acid palmitate was without effect. Arachidonate, linoleate, and oleate each induced the translocation of protein kinase C activity from the soluble fraction to the membrane fraction of colonic mucosa, an index of enzyme activation. The translocation of protein kinase C induced by unsaturated fatty acids occurred both in vivo after intracolonic instillation of these agents and in vitro upon incubation of isolated colonic crypt epithelium with fatty acids. The effects of the unsaturated fatty acids on both enzyme translocation and colonic epithelial proliferative activity were suppressed by 1-(5-isoquinolinyl)-2-methylpiperazine, an inhibitor of protein kinase C activity. Unsaturated fatty acids directly stimulated soluble colonic mucosal protein kinase C activity when added to the enzyme assay mixture. This action was blocked by 1-(5-isoquinolinyl)-2-methylpiperazine. However, unsaturated fatty acids also increased the breakdown of polyphosphoinositides when added to isolated colonic epithelium. The increase in polyphosphoinositide breakdown resulted in release of diacylglycerol, an endogenous activator of protein kinase C. Thus, unsaturated fatty acids may activate protein kinase C of colonic epithelium through either a direct intracellular effect or through an action on the cell membrane. The results support a role for protein kinase C in the stimulation of colonic epithelial proliferation by unsaturated fatty acids.
 ...
PMID:Role of activation of protein kinase C in the stimulation of colonic epithelial proliferation by unsaturated fatty acids. 313 25

Two outbred lines of CD-1 mice were developed using males and females in an initiation (dimethylbenz[a]anthracene; DMBA), promotion (12-O-tetradecanoylphorbol-13-acetate; TPA) challenge, posttumorigenesis breeding protocol. Our results indicate that the phorbol ester-sensitive (PESTI) line developed tumors at a rate 4.1 times faster than the CD-1 parental line, while the phorbol ester-resistant (PERTI) line developed tumors at a rate 36 times slower than the CD-1 parents. The average number of tumors per mouse reached levels of 27.5 at 12 wk in the PESTI line, 0.1 at 16 wk in the PERTI line, and 6.7 at 16 wk in the CD-1 line. Biochemical tests showed that the PESTI line had both a high basal level and an enhanced epidermal ornithine decarboxylase (E.C. 4.1.1.17) response to TPA, the latter being nine times that of the PERTI line at their maximum dosages. An autoradiographic analysis of in vivo epidermal cell protein phosphorylation indicated marked differences in basal protein phosphorylation profiles (with high phosphate incorporation, PERTI, 112.7, 95.5, 64.4, 40.8, 18.6, 17.4, and 12.3 kDa; PESTI, 64.4, 40.8, 31.8, and 12.3 kDa) as well as TPA-dependent changes in these profiles (difference from basal levels, PERTI, 31.8 and 12.8 kDa; PESTI, 139.6, 126.3, 37.2, and 18.6 kDa). These heterogeneous profiles indicate strong genetic segregation of these protein kinase C target substrates.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Tumorigenic and molecular characterization of novel phorbol ester-resistant and -sensitive lines of mice. 315 Dec 59


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>