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)

We report immunohistochemical evidence for the overexpression of protein kinase C in various proliferative diseases of human thyroid. Immunohistochemical characterization of various surgically removed thyroid tissues, viz., cancer tissues: papillary carcinoma and follicular carcinoma; adenoma tissues: tubular, trabecular and colloid adenomas; adenomatous goiter; and normal thyroid was done using the monospecific monoclonal antibodies MC-1a, MC-2a and MC-3a, each of which is specific for types I, II and III isozymes of protein kinase C, respectively. For protein kinase C type II, a remarkable difference in staining intensity was noted between the cancerous and normal tissues. The cytoplasm of papillary and follicular carcinoma cells stained more intensely than that of normal thyroid cells. In the benign tumor and adenomatous goiter tissues, stronger staining was noted in the papilliform-proliferating portion and cubic epithelial cells. In the normal thyroid tissues, epithelial cells of greater height were more strongly stained than simple squamous epithelial cells. These results indicated that protein kinase C type II isozyme is expressed in larger amounts in cancerous and proliferative tissues of the human thyroid.
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PMID:Immunohistochemical evidence for the overexpression of protein kinase C in proliferative diseases of human thyroid. 180 90

During the last decade, progress in chemical carcinogenesis research has been substantial, and understanding the cellular changes and molecular causes of initiation, promotion, and malignant conversion appears to be within reach. Cancer begins as a carcinogen-induced genetic change in a single cell. The interaction of a particular carcinogen with specific genetic sites results, in part, from selectivity of metabolically activated carcinogens for particular nucleosides or gene sequences. In turn, modification of the molecular structure at specific genetic loci will have tissue-specific and species-specific consequences dependent on the expression of a particular gene, its sequence, and the function of the gene product in the target cell. It is likely that inactivation of regulatory regions, genomic rearrangements, and point mutations in coding sequences all can result in an altered cell phenotype. The rasH gene (and perhaps other members of the ras gene family) appears to be a common target for coding sequence mutations in the initiation of carcinogenesis in several organ sites and species by specific carcinogens. Whatever genetic mechanisms are involved, an initiated cell phenotype common to many epithelial cell types is observed. Initiated cells have an altered program of terminal differentiation, are resistant to cytotoxic substances or show altered requirements for specific growth factors or nutrients. These cells would have a selective growth advantage in cytostatic or cytotoxic situations or under conditions favoring terminal differentiation. Tumor promoters, some acting through specific cellular receptors, produce a tissue environment conductive to the selective clonal outgrowth of the initiated cell population resulting in a clinically evident premalignant lesion. The tissue specificity for most promoters depends on the ability of a particular agent to produce the selective conditions required for the initiated phenotype of that organ. At the molecular level, phorbol ester tumor promoters bind to and activate protein kinase C and transduce signals through this second-messenger pathway. Heterogeneity in the species of protein kinase C molecule expressed by normal and initiated epidermal cells could account for the differential response pattern observed in these cell types during skin tumor promotion. Malignant conversion of benign tumors requires further genetic changes in the tumor cell. Such changes could result from inherent instability in the genome of initiated cells, from spontaneous mutations more likely to occur in the expanding population of proliferating benign tumor cells, or by additional exposure to exogenous genotoxic agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chemical carcinogenesis: from animal models to molecular models in one decade. 328 45

Ribonucleotide reductase is a highly regulated activity responsible for reducing ribonucleotides to deoxyribonucleotides, which are required for DNA synthesis and DNA repair. We have tested the hypothesis that malignant cell populations contain alterations in signal pathways important in controlling the expression of the two genes that code for ribonucleotide reductase, R1 and R2. A series of radiation and H-ras transformed mouse 10T1/2 cell lines with increasing malignant potential were exposed to stimulators of cAMP synthesis (forskolin and cholera toxin), an inhibitor of cAMP degradation (3-isobutyl-1-methylxanthine) and a biologically stable analogue of cAMP (8-bromo-cAMP). Dramatic elevations in the expression of the R1 and R2 genes at the message and protein levels were observed in malignant metastatic populations, which were not detected in the normal parental cell line or in cells capable of benign tumor formation. These changes in ribonucleotide reductase gene expression occurred without any detectable modifications in the rates of DNA synthesis, showing that they were regulated by a novel mechanism independent of the S phase of the cell cycle. Furthermore, studies with forskolin (a stimulator of the protein kinase A signal pathway) and the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (a stimulator of the protein kinase C signal pathway), alone or in combination, indicated that their effects on R1 and R2 gene expression in a highly malignant cell line were greater than when they were tested individually, suggesting that the two pathways modulating R1 and R2 gene expression can cooperate to regulate ribonucleotide reduction, and interestingly this can occur in a synergistic fashion. Also, a direct relationship between H-ras expression and ribonucleotide reductase gene expression was observed; analysis of forskolin mediated elevations in R1 and R2 message levels closely correlated with the levels of H-ras expression in the various cell lines. In total, these studies demonstrate that ribonucleotide reductase expression is controlled by a complex process, and malignant ras transformed cells contain alterations in the regulation of signal transduction pathways that lead to novel modifications in ribonucleotide reductase gene expression. This signal mechanism, which is aberrantly regulated in malignant cells, may be related to regulatory pathways involved in determining ribonucleotide reductase expression in a S phase independent manner during periods of DNA repair.
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PMID:Alterations in the cyclic AMP signal transduction pathway regulating ribonucleotide reductase gene expression in malignant H-ras transformed cell lines. 750 77

Murine keratinocytes expressing an oncogenic rasHa gene produce benign tumors in vivo and demonstrate altered responses to phorbol esters in vitro. Cultured keratinocytes transduced with the v-rasHa gene (v-rasHa keratinocytes) are resistant to Ca(2+)-induced terminal differentiation, a process that is dependent on protein kinase C (PKC) activation in normal keratinocytes. Five PKC isoforms expressed in keratinocytes (alpha, delta, epsilon, zeta, and eta) were examined for quantitative or qualitative changes in v-rasHa-transformed cells. No quantitative changes were detected, but PKC delta was tyrosine-phosphorylated in v-rasHa keratinocytes and in benign neoplastic keratinocyte cell lines expressing an activated allele of the c-rasHa gene. Analysis of phosphorylated and non-phosphorylated forms of PKC delta from keratinocytes indicated that phosphorylated PKC delta was not stimulated by phorbol ester treatment. The protein kinase inhibitor staurosporine was able to induce differentiation in v-rasHa keratinocytes and benign tumor cell lines, and concomitantly tyrosine phosphorylation of PKC delta decreased. This interaction between tyrosine kinases and PKC delta in cells expressing an oncogenic rasHa gene may represent a molecular block to differentiation in neoplastic keratinocytes.
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PMID:Expression of an oncogenic rasHa gene in murine keratinocytes induces tyrosine phosphorylation and reduced activity of protein kinase C delta. 825 22

Cell growth regulation by fibroblast growth factors (FGFs) is highly complex. The present study demonstrates a novel link between alterations in bFGF regulation during malignant conversion and the expression of ornithine decarboxylase, a key rate-limiting and regulatory activity in the biosynthesis of polyamines. H-ras transformed mouse 10T 1/2 cell lines exhibiting increasing malignant potential were investigated for possible bFGF-mediated changes in ornithine decarboxylase gene expression. Selective induction of ornithine decarboxylase gene expression was observed, since, in contrast to nontransformed 10T 1/2 cells and cells capable of only benign tumor formation, H-ras transformed metastatic cells exhibited marked elevations in ornithine decarboxylase message levels. Evidence for regulation of ornithine decarboxylase gene expression by bFGF at both transcription and posttranscription was found. Actinomycin D pretreatment of malignant cells prior to bFGF exposure inhibited the increase in ornithine decarboxylase message. Furthermore, striking differences in the rates of ornithine decarboxylase message decay were observed when cells treated with bFGF were compared to untreated control cells, with the half-life of ornithine decarboxylase mRNA increasing from 2.4 h in untreated cells to 12.5 h in cells exposed to bFGF. Evidence was also obtained for a cycloheximide-sensitive regulator of ornithine decarboxylase gene expression whose effect, in combination with bFGF, resulted in a further augmentation of ornithine decarboxylase gene expression. Furthermore, evidence is presented to suggest a possible role for G-protein-coupled events in the bFGF-mediated regulation of ornithine decarboxylase gene expression. The bFGF regulation of ornithine decarboxylase expression in H-ras transformed malignant cells appeared to occur independent of protein kinase C-mediated events. These results show that bFGF can modulate ornithine decarboxylase gene expression in malignant H-ras transformed cells and further suggests a mechanism of growth factor stimulation of malignant cells wherein early alterations in the regulatory control of ornithine decarboxylase gene expression are critical.
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PMID:Basic fibroblast growth factor selectively regulates ornithine decarboxylase gene expression in malignant H-ras transformed cells. 870 96

This study used the induction of squamous cell carcinomas on mouse skin as an experimental model to evaluate molecular and biochemical changes that contribute to the neoplastic phenotype. The study was facilitated by the development of keratinocyte cell culture assays that reproduce each stage of the carcinogenesis process, by discoveries of stage-specific genetic and epigenetic changes and by application of pharmacological and molecular tools that modify each step. An early event in the transformation of keratinocytes involves mutation and activation of the rasHa gene, producing a benign tumor. The phenotypic consequences of ras mutations are mediated by activation of the epidermal growth factor receptor (EGFR), upregulation of protein kinase C (PKC) alpha and AP-1 mediated transcriptional activity and inactivation of PKC delta through tyrosine phosphorylation. These changes in benign tumors are manifested by hyperproliferation (EGFR), aberrant expression of keratinocyte genes (PKC alpha and AP-1) and delayed terminal differentiation (PKC delta). Accumulated chromosomal abnormalities, multifocal phenotypic changes and alterations in gene expression are associated with premalignant progression. Upregulation of the fos gene and AP-1 transcriptional activity causes malignant conversion of benign keratinocytes. In the absence of c-fos, benign tumor cells fail to upregulate secreted angiogenic and proteolytic factors and this may prevent malignant conversion. These pathways provide targets for preventive strategies to interrupt the process of carcinogenesis prior to the evolution of the fully malignant tumor.
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PMID:The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis. 965 22

Protein kinase C family consists of 11 isoforms, classified into 3 categories according to their structure and mechanisms of activation. These isoenzymes are involved in processes, which maintain intracellular homeostasis. Alterations in activity, amount or distribution of protein kinase C (PKC) isoenzymes may cause cellular proliferation or induce apoptosis. We have studied and compared the expression levels of several PKC isoforms in benign prostatic hyperplasia (BPH) and prostate cancer (PCa). These are PKCs alpha (alpha), beta (beta), delta (delta), epsilon (epsilon), zeta (zeta), eta (eta), which have been detected as major isoforms in prostate tissue. Paraffin sections of 25 benign prostatic hyperplasia (BPH) and 25 of prostatic carcinoma (PCa) were examined for expression of PKC alpha, beta, delta, epsilon, zeta, and eta. Expression of PKC beta was examined in additional 3 BPH and 3 PCa using Western blot analysis. We found a significant high level of expression of PKC isoforms alpha, beta, epsilon and eta in PCa compared to BPH (p<0.01). Using backward logistic regression, we found changes in PKC epsilon expression to be most significant between malignant compared to benign tumor tissue specimens. Immunostaining for PKCs alpha, beta and eta in addition to PKC epsilon may aid in distinguishing between benign and malignant prostatic disease.
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PMID:Expression of protein kinase C isoenzymes in benign hyperplasia and carcinoma of prostate. 1471 62