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)

Epidemiologic studies suggest that the consumption of cruciferous vegetables is associated with a reduced risk for several types of cancer including cancer of colon. Experimental studies indicate that dithiolthiones, naturally occurring substances in cruciferous vegetables, possess anticarcinogenic properties. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a substituted dithiolthione, has been tested for its chemopreventive activity. We studied the effect of dietary oltipraz on liver and colonic mucosal enzymes and DNA adducts to evaluate the modulating role of this agent during the early period of azoxymethane (AOM)-induced carcinogenesis. At 6 weeks of age, groups of animals were fed the AIN-76A diet containing 0 and 300 ppm oltipraz. At 8 weeks of age, all of the animals except vehicle-treated animals were administered a subcutaneous injection of AOM (15 mg/kg body wt/week for 2 weeks). Animals intended for vehicle treatment were administered normal saline subcutaneously. Fifteen hours after the second AOM injection, six animals each from control oltipraz diet groups were sacrificed and liver and colonic mucosa from each animal were used for DNA adduct analysis. Animals intended for liver and colonic mucosal glutathione S-transferase, tyrosine specific protein kinase (TPK), and ornithine decarboxylase (ODC) enzyme assays were killed 5 days after the second AOM or saline injection. The results of this study indicated that dietary oltipraz significantly increased liver (P less than 0.001) and colonic mucosal (P greater than 0.05) weights, but had no effect on body weights (P greater than 0.05). In saline-treated animals, feeding of oltipraz significantly increased the cytosolic glutathione S-transferase (P less than 0.001) and ODC (P less than 0.05) activities in the liver and colon when compared with those fed the control diet. Although our unpublished results indicate an inhibitory role of oltipraz when fed during the initiation and postinitiation phases of intestinal carcinogenesis, the increased ODC activity may indicate a possible role of oltipraz in colon tumor promotion. Additional studies are indicated to test the antitumor properties of oltipraz administered during the postinitiation phases. AOM treatment significantly increased the TPK (P less than 0.0001) and ODC (P less than 0.01) activities in the liver and colon of animals fed the control diet. Dietary oltipraz significantly suppressed the AOM-induced TPK (P less than 0.001) activities in liver and colon and ODC (P less than 0.01) activity of colon. Analysis of nucleic acid bases, O6-methylguanine, and 7-methylguanine revealed that dietary oltipraz significantly (P less than 0.05) inhibited the AOM-induced adduct species. These results suggest that dietary oltipraz enhances the colonic and liver glutathione S-transferase activity and reduced the formation of DNA adducts. In addition, dietary oltipraz modulates liver and colonic ODC and TPK activities that have been shown to play a role in tumor promotion.
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PMID:Effect of oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] on azoxymethane-induced biochemical changes related to early colon carcinogenesis in male F344 rats. 202 Jun 72

Preservation of the shape and the integrity of multicellular eukaryotes needs rigorous cell proliferation monitoring. During the prereplicative G1 phase, a finely adjusted and specific control supervises the proliferant/non proliferant states of the cells. Some molecular mechanisms of growth regulation have been identified in recent years. Changes in normal cell attachment on extracellular matrix and intercellular chemical signalling (secretion of informative molecules) activate intracellular signals for division. The transduction mechanisms of the extracellular signalling to the nucleus have been partially elucidated for steroid hormones and growth factors. Molecular biology research and proto-oncogene discoveries have led to considerable progress in understanding the role of these normal genes in the control of cellular proliferation. The initiation of the response to extracellular factors requires: i), direct transducers (specific binding of the steroid hormone on its cytoplasmic or nuclear receptor and high affinity binding of this activated complex to specific DNA sequences); and ii) indirect transducers (binding of growth factors on extracellular domains of specific receptor proteins which convert this extracellular event into several intracellular signals, secondary messengers, protein kinases and specific nuclear regulatory factors). Whatever the transduction system, nuclear events control transcription of growth regulatory genes. The series of enzymatic reactions set in motion by indirect transduction systems require strict regulation systems, the diversity and the complexity of which has been perceived in studies on jun and fos gene families. Each proliferation step is governed by growth stimulators and growth inhibitors, the transformation of normal cells to cancer cells resulting from alterations of these regulatory process. Independent of extracellular stimuli and of their transfer to the nucleus, intracellular controls coordinate cell cycle phases (G1, S, G2 and M) to produce daughter cells identical to the original cell. Two control points are particularly critical: one in G1 (the "start" point) and the other in G2 just before mitosis. Although intermediate steps between extracellular and intracellular controls are still unknown, yeast gene analyses have allowed determination of molecular regulatory mechanisms implicated in the passage of these critical points. A considerable advance was made by the discovery that some of the involved components presented strong sequence and function homologies in organisms from yeast to man, suggesting a phyllogenetically conserved mechanism. It seems likely that the phosphorylation state of protein p34, its association with a G1-phase specific cyclin or a M-phase specific cyclin, and its protein kinase activity regulate the proliferation state of higher eukaryotic cells. In spite of significant advances, much research is still necessary to elucidate all the mechanisms involved in cell cycle control.
Bull Cancer 1991 Jan
PMID:[Different regulation systems of cell cycle events (dysregulation of these events in the tumoral cell)]. 202 83

Eukaryotic cell cycle progression during meiosis and mitosis is extensively regulated by reversible protein phosphorylation. Many cell surface receptors for mitogens are ligand-stimulated protein-tyrosine kinases that control the activation of a network of cytoplasmic and nuclear protein-serine (threonine) kinases. Over 30 plasma membrane associated protein-tyrosine kinases are encoded by proto-oncogenes, i.e., genes that have the potential to facilitate cancer when disregulated. Proteins such as ribosomal protein S6, microtubule-associated protein-2, myelin basic protein, and casein have been used to detect intracellular protein-serine (threonine) kinases that are activated further downstream in growth factor signalling transduction cascades. Genetic analysis of yeast cell division control (cdc) mutants has revealed another 20 or so protein-serine (threonine) kinases. One of these, specified by the cdc-2 gene in Schizosaccharomyces pombe, has homologs that are stimulated during M phase in maturing sea star and frog oocytes and mammalian somatic cells. Furthermore, during meiotic maturation in these echinoderm and amphibian oocytes, this is followed by activation of many of the same protein-serine (threonine) kinases that are stimulated when quiescent mammalian somatic cells are prompted with mitogens to traverse from G0 to G1 phase. These findings imply that a similar protein kinase cascade may oversee progression at multiple points in the cell cycle.
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PMID:Protein kinase cascades in meiotic and mitotic cell cycle control. 208 30

Colonic neoplasia provides an opportunity to study tumor progression because most carcinomas arise from adenomas (polyps), which, in turn, arise from normal epithelia. The malignant potential of adenomas varies with size, histology, and degree of dysplasia. Polyps that are less than 2 cm with villous architecture and severe dysplasia are most likely to contain carcinoma. Previous studies demonstrated that the in vitro protein-tyrosine kinase activity of pp60c-src from colon carcinomas is significantly higher than that from adjacent normal mucosa. Here we report that the protein kinase activity of pp60c-src is also elevated in colonic polyps. Activity is highest in malignant polyps and in greater than 2-cm benign polyps that contain villous structure and severe dysplasia. Thus, pp60c-src activation occurs in benign polyps that are at greatest risk for developing cancer. These data suggest that activation of the protooncogene product pp60c-src may be an important event in the genesis of human colon carcinoma.
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PMID:Activation of the pp60c-src protein kinase is an early event in colonic carcinogenesis. 210 87

The present study provides evidence that rat brain protein kinase C elicits a phosphotransferase activity towards histone and undergoes autophosphorylation in the absence of phosphatidylserine. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate binds to and activates protein kinase C in a phospholipid-free reaction. The apparent activation constant (Ka = 2.7 nM) is not modified by the absence of phospholipid but the maximum velocity is greatly decreased. The phosphotransfer reaction to exogenous substrates occurs in 0.5 mM ethylene-bis(oxyethylenenitrilo)tetraacetic acid, although autophosphorylation in these conditions requires the presence of Ca2+. The protein kinase C inhibitor (1-(5-isoquinolinesulfonyl)-2-methylpiperazine inhibits the reaction, whereas the cAMP-dependent protein kinase inhibitor is ineffective. In contrast to diacylglycerol, which is a poor activator, unsaturated fatty acids potently activate the phospholipid-free reaction. Moreover, the substrate specificity is markedly changed, e.g., myelin basic protein and histone types VI-S and VII-S appear to be relatively better substrates in the phospholipid-free reaction. The data presented indicate that protein kinase C (or some individual isoforms) may function, at least partially, without binding to membrane phospholipid and suggest that this novel characteristic of phorbol esters may account for their tumor-promoting activity.
Cancer Res 1990 Apr 01
PMID:Phorbol esters mediate phospholipid-free activation of rat brain protein kinase C. 210 68

We examined pp60c-src protein kinase activity in human gastric carcinoma cell lines and gastric carcinoma tissues as well as normal mucosa. pp60c-src kinase activity was detected in all 5 carcinoma cell lines at various levels. Of 16 gastric carcinoma tissues, 8 showed higher pp60c-src kinase activity in tumor tissues than in corresponding normal mucosa. However, the levels of expression of pp60c-src detected by Western blotting were not always consistent with the activities of pp60c-src protein kinase. These findings suggest that the increase in pp60c-src protein kinase activity might be brought about by post-translational changes.
Int J Cancer 1990 May 15
PMID:pp60c-src protein kinase activity in human gastric carcinomas. 211 May 50

Inhibition by alpha-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamamide (ST 638) of tyrosine-specific protein kinase was examined using epidermal growth factor (EGF)-treated A431 cells at the concentration of 25 to 100 microM. ST 638 had negligible effects on the growth and morphology of A431 cells and on EGF binding to its receptor, and subsequent down-regulation of the receptor. ST 638 specifically inhibited EGF-induced phosphorylation of tyrosine residues of whole cell proteins in a dose-dependent manner without affecting the phosphorylation of serine and threonine residues. ST 638 greatly inhibited the EGF-induced phosphorylation of lipocortin I at 25 microM, and yet had a negligible effect on the EGF-induced phosphorylation of EGF receptor. Neither the amount of [35S]methionine-labeled lipocortin I nor the serine/threonine phosphorylation level of fodrin beta-subunit was affected by the same concentration of ST 638. These results indicate that the phosphorylation of lipocortin I is not relevant to the transformation of A431 cells. In cell lines transformed by src or fgr oncogene encoding tyrosine kinase, ST 638 also inhibited phosphorylation of calpactin I (p36) without affecting that of the oncogene products. Two-dimensional polyacrylamide gel electrophoresis showed that ST 638 specifically inhibited the EGF-induced phosphorylation and dephosphorylation of cellular proteins in A431 cells.
Jpn J Cancer Res
PMID:A tyrosine-specific protein kinase inhibitor, alpha-cyano-3-ethoxy-4-hydroxy-5-phenylthiomethylcinnamamide, blocks the phosphorylation of tyrosine kinase substrate in intact cells. 214 51

Cells respond to proliferative signals generated by growth factors and oncogenes with a complex array of biochemical and physiological events, culminating in DNA synthesis and cell division. One of the molecules thought to be critical for the transmission and amplification of mitogenic signals from the cell surface to the nucleus is the proto-oncogene product Raf-1. Raf-1 is a serine-threonine kinase that is itself phosphorylated in response to mitogenic stimulation. The phosphorylation state of Raf-1 appears to modulate its kinase activity. Experiments linking Raf-1 to other characterized components of the signal transduction machinery are reviewed here.
Cancer Cells 1990 Dec
PMID:The Raf-1 kinase as a transducer of mitogenic signals. 215 Sep 16

Some genital human papillomavirus (HPV) types, such as 16 and 18, are highly associated with malignant cervical tumors while others, such as HPV 6, are only rarely found in these malignancies. The E7 oncoproteins of HPV 6, 16 and 18 each have a 17 amino acid region with striking homology to adenovirus E1a and SV40 LT. E1a, LT and the E7 oncoprotein of HPV16 all bind the cellular Rb protein in vitro, and for E1a and LT this region of homology contains sequences essential for interaction with Rb. We have now found that in HPV 16 E7 this region (amino acids 21-37) contains two separate biochemical activities, each of which contributes to E7-mediated transformation. Rb binding was localized to the N terminus of this region, while the C terminus was shown to serve as a substrate for casein kinase (CK) II, which phosphorylated serine-31 and serine-32. Replacement of the two serines by non-phosphorylatable amino acids led to a reduction in transforming activity and abolished phosphorylation but did not affect Rb binding. Rb binding and CK II phosphorylation were also examined for the E7 proteins of HPV 6 and HPV 18. HPV 16 and 18 E7 bound similar amounts of Rb, but HPV 6 E7 consistently bound less. Phosphorylation rates also varied, with HPV 18 E7 being 2-fold faster than HPV 16 E7, which in turn was 2-fold faster than HPV 6 E7. We conclude that Rb binding and phosphorylation of E7 by CKII are independent activities which are required for efficient transformation by E7 and that these activities correlate directly with the relative oncogenic potential of these viruses.
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PMID:The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation. 215 75

In this report we show that the mRNA level for the estrogen receptor (ER) is regulated by 8-bromo cyclic AMP (8-Br-cAMP) and human chorionic gonadotropin in a mouse tumor Leydig cell line (MA-10 cells). When the MA-10 cells were cultured in the presence of the cAMP analogue for varying time periods, a transient increase in the level of ER mRNA was observed. Short time incubation (0-2 h) with 8-Br-cAMP enhanced the expression of ER mRNA (2-fold), whereas longer times of incubation (6 h) had the opposite effect (the level of ER mRNA was reduced by 60-70%). The inhibitory effect of 8-Br-cAMP on ER mRNA was not counteracted by aminoglutethimide, an inhibitor of steroidogenic enzymes, indicating that this effect is not mediated via steroids (progesterone). Treatment of 8-Br-cAMP for 6 h caused a concentration-dependent inhibition of ER mRNA with a half-maximal effect of approximately 150 microM. Increasing concentrations of human chorionic gonadotropin for 6 h was also associated with a biphasic effect on the ER mRNA level. Low concentrations (0.20-0.40 ng/ml) increased ER mRNA in the MA-10 cells whereas the highest concentration (20 ng/ml) caused a suppression of this mRNA. In contrast to the biphasic effects observed for the ER mRNA, the level of the regulatory subunit type II beta of the cAMP-dependent protein kinase (protein kinase A) was enhanced in a concentration-dependent manner by human chorionic gonadotropin. Furthermore, 8-Br-cAMP stimulated the mRNA for regulatory subunit type II beta (10- to 20-fold) by all concentrations examined (50-1000 microM). The observations reported here indicate that the expression of ER mRNA is regulated both by endogenously formed and exogenously added cAMP and that there may exist regulatory loops between the steroid and the cAMP/protein kinase A systems.
Cancer Res 1990 Mar 01
PMID:Biphasic regulation of the messenger ribonucleic acid coding for the estrogen receptor by cyclic adenosine 3':5'-monophosphate in tumor Leydig cells. 215 26


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