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)

Cellular oncogenes comprise a small family of genes, highly conserved throughout vertebrate evolution, that code for proteins with diverse functions including DNA binding, protein kinase, and cellular growth factor activities. Cellular oncogenes are important in certain aspects of the proliferation and differentiation of normal cells. Under some circumstances these genes may also induce malignant transformation of normal cells. Various mechanisms may underlie their involvement in carcinogenesis. Incorporation of all, or part of, cellular oncogenes into RNA tumor viruses, mutations in gene structure, or translocation of cellular oncogenes from one chromosome to another may all be associated with the induction of malignant change in cells. In some of these situations altered oncogene products are made. Knowledge about the biology of oncogenes may lead to improved techniques for cancer detection and perhaps new approaches to cancer treatment.
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PMID:Oncogenes: implications for the diagnosis and treatment of cancer. 633 Dec 42

Although gene regulatory mechanisms in eukaryotic cells are complex, some progress is being made in understanding them. Chromosomal proteins may play a significant role in genome function and gene control. More specifically, a central role may be played by the nuclear nonhistone proteins. It appears that both viral transformation and steroid hormone action may be associated with the phosphorylation of these proteins. Recent studies have revealed that some oncogenic viruses are capable of producing viral transforming proteins with protein kinase activity. This suggests how they may subvert normal gene regulatory mechanisms. Furthermore, the effects of the steroid-receptor complex on nuclear nonhistone proteins may be similar to the effects of these viral transforming proteins, but in a controlled sense. A model of gene-regulatory, nuclear phosphorylation reactions is formulated which suggests how some oncogenic viruses may control normal gene regulatory mechanisms and how steroid hormones may interact with these same mechanisms. Such a model may reveal how disruption of these same mechanisms leads to carcinogenesis.
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PMID:Gene control by phosphoproteins: a theoretical model for eukaryotic DNA regulation. 636 89

An endogenous protein of human cells pp60c-src, which is closely related to the product of the transforming gene of Rous sarcoma virus, pp60v-src, has been quantitated by measuring its enzymatic activity in an immunoglobulin G protein kinase assay. The influence of normal developmental processes on pp60c-src expression was assessed by comparative analysis of various adult and fetal human tissues. The maximal difference detected was a 2- to 3-fold-enhanced activity in fetal muscle compared with adult muscle. Organ-specific variations in the enzyme level were observed. Highest activity was found in brain, followed by kidney, lung, muscle, and connective tissue. Since overexpression of the cellular counterparts of viral-transforming genes may play a role in carcinogenesis, pp60c-src kinase was measured in nine spontaneous human sarcomas and 21 mammary carcinomas. Compared with the respective normal tissues and human diploid fibroblasts, 4- to 20-fold-enhanced activities were observed in one-third of the sarcomas and carcinomas. The remainder showed no or insignificantly elevated activity. The enzymes from normal and malignant tissues were indistinguishable from the virus-coded enzyme with respect to specificity for divalent cations and a predominance of phosphorylation in tyrosine. Patients carrying tumors with high pp60c-src protein kinase activity did not develop kinase-reactive antibodies against pp60c-src or pp60v-src.
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PMID:Expression of pp60c-src protein kinase in adult and fetal human tissue: high activities in some sarcomas and mammary carcinomas. 640 27

The phosphorylation of rabbit liver microsomal cytochrome P-450 LM2 by catalytic subunit of cyclic AMP-dependent protein kinase (W. Pyerin et al. (1983) Carcinogenesis 4, 573) has now been studied in detail with purified soluble form of cytochrome P-450 as well as with the purified protein incorporated into model membranes. The apparent Km values for P-450 of the phosphorylation reaction in all experimental systems were in a range of 2-8 microM, while the Vmax values were dependent on the state of P-450. Upon phosphorylation, the reconstituted enzyme activities with benzphetamine (N-demethylation) and 7-ethoxycoumarin (O-deethylation) as substrates were reduced to 30-40% of control.
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PMID:Phosphorylation of rabbit liver cytochrome P-450 LM2 and its effect on monooxygenase activity. 646 31

Although gene regulatory mechanisms in eukaryotic cells are complex, some progress is being made in understanding them. Chromosomal proteins may play a significant role in genome function and gene control. More specifically, a central role may be played by the nuclear nonhistone proteins. It appears that both viral transformation and steroid hormone action may be associated with the phosphorylation of these proteins. Recent studies have revealed that some oncogenic viruses are capable of producing viral transforming proteins with protein kinase activity. This suggests how they may subvert normal gene regulatory mechanisms. Furthermore, the effects of the steroid-receptor complex on nuclear nonhistone proteins may be similar to the effects of these viral transforming proteins, but in a controlled sense. A model of gene-regulatory, nuclear phosphorylation reactions is formulated which suggests how some oncogenic viruses may control normal gene regulatory mechanisms and how steroid hormones may interact with these same mechanisms. Such a model may reveal how disruption of these same mechanisms leads to carcinogenesis.
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PMID:Gene control by phosphoproteins: a theoretical model for eukarotic DNA regulation. 672 23

Most chemical carcinogens require activation by polysubstrate monooxygenase. The phosphorylation of essential components of this cytochrome P-450 monooxygenase system, isolated from rabbit liver microsomes, cytochrome P-450 (LM2) and cytochrome reductase, was tested using two different protein kinases. One of the kinases, a cyclic AMP-independent phosvitin kinase (kinase P), was inactive in all systems tested. However, the catalytic subunit of a cyclic AMP-dependent protein kinase (kinase C) catalyzed phosphoryl group transfer to both proteins, but to different extents. Cytochrome P-450 was phosphorylated when added as sole component and also when in the presence of P-450 reductase and phosphatidylcholine. In contrast, the weak phosphorylation of P-450 reductase was reduced considerably in a complete reconstituted system containing P-450 and phosphatidylcholine. The inclusion of kinase P did not alter these results which excludes the possibility that these kinases participate in a sequential phosphorylation mechanism. The monooxygenase constituents themselves were without kinase activity. When hepatic microsomes were isolated in presence of the phosphatase inhibitor sodium fluoride no significant change in monooxygenase (7-ethoxycoumarin O-deethylation) activity was observed, whilst after preincubation with either acid or alkaline phosphatase a significant reduction in monooxygenase activity was measured. Thus, cytochrome P-450 (LM2) is phosphorylatable by protein kinase C and the catalytic activity of polysubstrate monooxygenase decreases after preincubation of microsomes with phosphatases.
Carcinogenesis 1983
PMID:Phosphorylation of cytochrome-P-450-dependent monooxygenase components. 685 Sep 89

Computer analysis of protein phosphorylation sites sequence revealed that transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of the proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of protein kinase FA/glycogen synthase kinase-3 alpha (kinase FA/GSK-3 alpha) (a member of the PDPK family) has been optimized for human thyroid tissue and used to demonstrate for the first time significantly increased (P < 0.001) activity in thyroid carcinoma (24.2 +/- 2.8 units/mg of protein) (n = 7), thyroid adenoma (14.5 +/- 2.2 units/mg of protein) (n = 6), and thyroid hyperplasia (8.0 +/- 2.4 units/mg of protein) (n = 5) when compared to five normal controls (4.1 +/- 1.8 units/mg of protein). Immunoblotting analysis further revealed that increased activity of kinase FA/GSK-3 alpha in thyroid tumor cells is due to overexpression of the protein synthesis of the enzyme. Taken together, the results provide initial evidence that overexpression of protein level and cellular activity of kinase FA/GSK-3 alpha is involved in human thyroid tumor cell dedifferentiation, supporting an association of PDPK with neoplastic transformation and tumorigenesis. Since kinase FA/GSK-3 alpha may function as a possible regulator of transcription factors/protooncogenes, kinase FA/GSK-3 alpha may therefore play an important role in thyroid cell carcinogenesis, especially in its differentiation.
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PMID:Overexpression of cellular activity and protein level of protein kinase FA/GSK-3 alpha correlates with human thyroid tumor cell dedifferentiation. 759 69

Four cyclin-dependent kinase inhibitors called p15, p16, p21 and p27 have been identified in mammals. Because these proteins participate in the control of cell cycle, they are potential targets for somatic mutations during carcinogenesis. In order to document the prevalence of p15 and p16 alterations in gliomas, we looked for loss of heterozygosity of chromosome 9p where these genes are localized. Allelic losses were observed in 31 of 44 investigated cases. In all cases they involved the p15/p16 locus. We then looked for mutations in the p16 and p15 genes in 46 gliomas. A total of three DNA variants were observed which were all present in the matched constitutional DNA. They may be unrelated to tumor development. A single somatic mutation was detected. It involved a C to G substitution in codon 93 of p16 and is predicted to change a threonine into an arginine. Taken together, these data indicate that inactivation by point mutation of these two cyclin-dependent kinase inhibitors is uncommon in glial tumor carcinogenesis, but that there may be a tumor suppressor gene on 9p in the vicinity of p16 and p15 genes.
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PMID:Frequent loss of heterozygosity on chromosome 9, and low incidence of mutations of cyclin-dependent kinase inhibitors p15 (MTS2) and p16 (MTS1) genes in gliomas. 763 Jun 44

Mitogen-activated protein kinases (MAPKs) play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAPK cascade, which includes MEK (also known as MAP kinase kinase), Raf-1, and Ras. In this study, we examined whether constitutive activation of the MAPK cascade was associated with the carcinogenesis of human renal cell carcinomas in a series of 25 tumors and in corresponding normal kidneys. Constitutive activation of MAPKs in tumor tissue, as determined by the appearance of phosphorylated forms, was found in 12 cases (48%), and this activation was confirmed by a direct in vitro kinase assay of immunoprecipitate using myelin basic protein as the substrate. The phosphorylation of MEK and of Raf-1, as monitored by a mobility shift in SDS-PAGE, which is reportedly associated with the activation of these kinases, occurred in 9 of 18 cases (50%) and in 6 of 11 cases (55%) respectively. The activation of MAPKs was correlated with MEK activation (P = 0.0045) and with Raf-1 activation (P = 0.067). Furthermore, overexpression of MEK was found in 13 of 25 cases (52%) by Western blot analysis, and this overexpression was associated significantly with MAPK activation (P = 0.034). No mutations were noted in H-,K-, or N-ras genes by PCR direct sequencing in any of the 25 tumor samples. Of the patients studied, 8 of 18 (44%) stage pT2 patients and four of six (67%) stage pT3 patients showed MAPK activation. The single stage pT1 patient did not evidence MAPK activation. Furthermore, one of seven (14%) grade 1 patients, 9 of 13 (69%) grade 2 patients, and two of five (40%) grade 3 patients showed MAPK activation (grade 1 versus grades 2 and 3, P = 0.046). Our results suggest that constitutive activation of MAPKs may be associated with the carcinogenesis of human RCCs.
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PMID:Constitutive activation of mitogen-activated protein (MAP) kinases in human renal cell carcinoma. 766 95

Fusarium moniliforme (FM) is a major fungal pathogen of corn and is involved with stalk rot disease. FM is widely spread throughout the world, including the United States. Most strains of FM produce several mycotoxins, the most prominent of which is called fumonisin. Recent epidemiological studies indicated that ingestion of fumonisin correlates with a higher incidence of esophageal cancer in Southern and Northern Africa and China. Furthermore, fumonisin causes a neurodegenerative disease in horses, induces hepatic cancer in rats, and induces pulmonary edema in swine. Considering that high levels of fumonisin have been detected in healthy and diseased corn grown in the United States, fumonisin may pose a health threat to humans and livestock animals. Structurally, fumonisin resembles sphingolipids which are present in the membranes of animal and plant cells. At the present time, very little is known concerning the mechanism by which fumonisin elicits its carcinogenic effect. Our studies indicate that fumonisin represses expression of protein kinase C and AP-1-dependent transcription. In contrast, fumonisin stimulated a simple promoter containing a single cyclic AMP response element. Since fumonisin did not alter protein kinase A activity, it appears that cyclic AMP response element activation was independent of protein kinase A. It is hypothesized that the ability of fumonisin to alter signal transduction pathways plays a role in carcinogenesis.
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PMID:Repression of protein kinase C and stimulation of cyclic AMP response elements by fumonisin, a fungal encoded toxin which is a carcinogen. 771 70


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