Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Resistance to multiple chemotherapeutic agents is a common clinical problem in the treatment of cancer: such resistance may occur in primary therapy or be acquired during treatment. The most commonly used antineoplastic agents in the treatment of disseminated breast cancer are adriamycin, methotrexate and cyclophosphamide. Cell lines selected for resistance to adriamycin often develop cross-resistance to structurally dissimilar antineoplastic drugs with different mechanisms of cytotoxic action; this phenomenon has been called pleiotropic or multidrug resistance (MDR). In vitro models of MDR have shown that this type of resistance is accompanied by a decrease in cellular drug accumulation, mediated by the over-expression of a 170 kD plasma membrane glycoprotein referred to as P170. Glycoprotein P170 is an energy-dependent multidrug efflux pump, whose activity can be inhibited in vitro by a variety of agents including verapamil, quinidine and reserpine. P170 is over-expressed also in some human malignancies, and evidence exists about its role in examples of clinical resistance in vitro. Clinical trials using verapamil, a calcium channel blocker which selectively enhances drug cytotoxicity in MDR cell lines, have been prompted for leukemia and ovarian cancer. In addition other approaches are the subject of current preclinical investigations. Several observations as well the phenomenon of "atypical" MDR in cell lines which do not overexpress P170, suggest that also other factors are involved in multidrug resistance. Qualitative or quantitative changes in the activity of topoisomerases, protein kinase-related systems and glutathione S-transferase, may confer pleiotropic resistance. As the role of these genes and their regulation is clarified, they may also serve as useful targets for pharmacologic intervention in the treatment of drug-resistant human tumors. The mechanisms involved in resistance to methotrexate and cyclophosphamide are less studied, particularly in vivo samples. Methotrexate resistance is probably a complex multifactorial phenomenon; in some cases it is due to an increase in the expression of the drug target dihydrofolate reductase, often as a result of gene amplification, but in other cases a transport defect of the methotrexate or alterations of the activity of different enzymes have been reported. Cyclophosphamide (CP) resistance has been attributed to an increased activity of two different enzymes, glutathione S-transferase, also involved in MDR phenotype, and aldehyde dehydrogenase, which catalyzes inactivation of CP in non cytotoxic metabolites. This paper reviews the current state of our knowledge of chemo-resistance and the utility of available markers to identify potentially resistant tumors in vivo; the strategies that might be used to overcome this phenomenon are also described.
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PMID:Chemoresistance in breast tumors. 168 Jun 89

Polymorphonuclear leukocytes (PMNL) release superoxide anions formed by a membrane-bound NADPH oxidase induced by stimulations. Properties of the inducers and their antagonists indicate that Ca2+, GTP-binding protein (G-protein), phospholipase C and Ca2+, phospholipid-dependent protein kinase (C-kinase) are mainly associated with the stimulation of receptors. Low concentrations of ATP induce the oxidase accompanied by the increase in the intracellular Ca2+ due to the flux from the medium and the storage site. ATP-gamma-S, UTP and ITP are effective but mononucleotides, dinucleotides, GTP and CTP are not. Leukotriene B4 (LTB4) which acts as a chemotactic agent and the inducer of the NADPH oxidase is catabolized. It is hydroxylated by a specific cytochrome P450 and then oxidized to a carboxy derivative by a cytosolic alcohol dehydrogenase and a microsomal aldehyde dehydrogenase in PMNL. Active NADPH oxidase was obtained by incubating membrane and cytosolic components of resting PMNL in the presence of sodium dodecyl sulfate (SDS). Two cytosolic components were obtained by an affinity chromatography on 2',5'-ADP Sepharose. One component is active in the presence of GTP or GTP-gamma-S and the other component in the presence of another cytosolic fraction.
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PMID:Metabolism of stimulated polymorphonuclear leukocytes. 254 77

The complete amino acid sequence of rat liver CoA-dependent methylmalonate semialdehyde dehydrogenase, the enzyme responsible for the oxidative decarboxylation of malonate- and methylmalonate semialdehydes to acetyl- and propionyl-CoA in the distal portions of the valine and pyrimidine catabolic pathways, has been deduced from overlapping cDNAs obtained by screening a lambda gt11 library with nondegenerate oligonucleotide probes synthesized according to PCR-amplified portions coding for the N-terminal amino acid sequence of the enzyme. Although unique because of its requirement for coenzyme A, the methylmalonate semialdehyde dehydrogenase clearly belongs to the aldehyde dehydrogenase superfamily of enzymes. Quantitation of mRNA and protein levels indicates tissue-specific expression of methylmalonate semialdehyde dehydrogenase. A large increase in expression of methylmalonate semialdehyde dehydrogenase occurs during 3T3-L1 preadipocyte differentiation into adipocytes. The complete amino acid sequence of rat liver branched-chain alpha-ketoacid dehydrogenase kinase, the enzyme responsible for phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase complex, was deduced from a cDNA cloned by a procedure similar to that described above for the methylmalonate semialdehyde dehydrogenase. Expression of the cDNA in E. coli yielded a protein that phosphorylated and inactivated the branched-chain alpha-ketoacid dehydrogenase complex. Very little sequence similarity between branched-chain alpha-ketoacid dehydrogenase kinase and other eukaryotic protein kinases could be identified. However, a high degree of similarity within subdomains characteristic of prokaryotic histidine protein kinases was apparent. Thus, this first mitochondrial protein kinase to be cloned appears closer, evolutionarily, to the prokaryotic histidine protein kinases than eukaryotic ser/thr protein kinases.
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PMID:Molecular cloning of the branched-chain alpha-keto acid dehydrogenase kinase and the CoA-dependent methylmalonate semialdehyde dehydrogenase. 835 11

Tyrosine kinase inhibitors have been widely used to probe the role of tyrosine phosphorylation in cellular signalling. These inhibitors exhibit an apparent specificity for tyrosine kinases over the serine/threonine kinases but little is known about their effects on other enzymes or biological systems. We demonstrate that genistein, erbstatin and alpha-cyanocinnamamides (tyrphostins) have inhibitory effects on fatty acid synthesis, lactate transport, mitochondrial oxidative phosphorylation and aldehyde dehydrogenase. We propose, therefore, that results obtained using tyrosine kinase inhibitors should be interpreted with caution, particularly if used at concentrations sufficient to inhibit these non-protein kinase-dependent events.
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PMID:Effects of tyrosine kinase inhibitors on protein kinase-independent systems. 842 54

A locust within chromosome XIII of Saccharomyces cerevisiae containing four genes upregulated by osmotic stress has been characterized. Two of the genes, but not their osmotic induction, were already described: the DNA damage-inducible gene DDR48 and the protease inhibitor gene PAI3. The two novel genes encode a cytoplasmic aldehyde dehydrogenase (ALD2) and a peptide of unknown function (SIP18). These genes form a cluster of two pairs of divergent promoters regulated by osmotic stress. The regulation of the divergent ALD2 and DDR48 genes, however, occurs by different mechanisms. ALD2 exhibits maximum induction with 0.3 M NaCl, negative regulation by protein kinase A and dependence on PBS2 and HOG1 protein kinases for osmotic induction. DDR48 requires 1 M NaCl for maximum induction and its expression in independent of PBS2 and HOG1 protein kinases and less sensitive to protein kinase A. PAI3 and SIP18 are as dependent on the above protein kinases as ALD2. Deletion analysis indicates that most of the regulation of the ALD2 promoter is mediated by a negative element counteracted by osmotic stress.
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PMID:A genomic locus in Saccharomyces cerevisiae with four genes up-regulated by osmotic stress. 880 20

We investigated the inhibitory effects of intracellular cyclic adenosine monophosphate (cAMP) levels in regulating class 3 aldehyde dehydrogenase (aldh3) gene expression using cultures of primary rat hepatocytes and transient transfection experiments with HepG2 cells. In addition to regulation by an Ah receptor-dependent mechanism, expression of many members of the Ah gene battery have been shown to be negatively regulated. As was seen for the cytochrome P450 (cyp1A1) gene, aldh3 is transcriptionally inducible by polycyclic aromatic hydrocarbons (PAH), and this induction involving function of the arylhydrocarbon (Ah) receptor is inhibited by the protein kinase C (PKC) inhibitors, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine di-HCl (H7) and staurosporine. However, PAH induction of ALDH-3 activity, protein, and mRNA was potentiated 2-4-fold by addition of the protein kinase A (PKA) inhibitors, N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide di-HCl (H8) and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide HCl (HA1004). These PKA inhibitors had no effect on the PAH induction of the cyp1A1. Protein kinase A activity of cultured hepatocytes was specifically inhibited by H8 and HA1004 in a concentration-dependent manner, but not by H7, and there was an inverse correlation observed between potentiation of PAH-induced aldh3 gene expression and inhibition of specific PKA activity by the PKA inhibitors. The cAMP analog dibutyryl cAMP, the adenylate cyclase activator forskolin, and the protein phosphatase 1 and 2A inhibitor okadaic acid all dramatically inhibited both PAH induction and H8 potentiation of PAH induction of aldh3 expression but had no effect on induction of cyp1A1 expression in cultured hepatocytes. Both basal and PAH-dependent expression of a chloramphenicol acetyltransferase expression plasmid containing approximately 3.5 kilobase pairs of the 5'-flanking region of aldh3 (pALDH3.5CAT) were enhanced 3-4-fold by the PKA inhibitor H8 but not by the PKC inhibitor H7 (>20 microM). cAMP analogs, activators of PKA activity, or protein phosphatase inhibitors diminished expression of the reporter gene in a manner identical to the native gene in cultured rat hepatocytes. Using deletion analysis of the pALDH3.5CAT construct, we demonstrated the existence of a negative regulatory region in the 5'-flanking region between -1057 and -991 base pairs which appears to be responsible for the cAMP-dependent regulation of this gene under both basal and PAH-induced conditions. At least two apparently independent mechanisms which involve protein phosphorylation regulate aldh3 expression. One involves function of the Ah receptor which requires PKC protein phosphorylation to positively regulate both aldh3 and cyp1A1 gene expression and the other a cAMP-responsive process which allows PKA activity to negatively regulate expression of aldh3 under either basal or inducible conditions.
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PMID:cAMP-dependent negative regulation of rat aldehyde dehydrogenase class 3 gene expression. 901 60

To study the mechanisms that control epithelial commitment and differentiation we have used undifferentiated HT-29 colon cancer cells and a subpopulation of mucus secreting cells obtained by selection of HT-29 cells in 10-6 M methotrexate (M6 cells) as experimental models. We isolated cDNAs encoding transcripts overexpressed in early confluent M6 cells regarding steady-state levels in HT-29 cells by subtractive hybridisation. Fifty-one cDNA clones, corresponding to 34 independent transcripts, were isolated, partially sequenced by their 5' end, and classified into four groups according to their identity: transcripts that included a repeated sequence of the Alu family (10 clones, among them those encoding ribonucleoprotein RNP-L and E-cadherin), transcripts encoded by the mitochondrial genome (nine clones), transcripts encoding components of the protein synthesis machinery (23 clones, including the human ribosomal protein L38 not previously cloned in humans) and nine additional cDNAs that could not be classified in the previous groups. These last included ferritin, cytokeratin 18, translationally controlled human tumour protein (TCHTP), mt-aldehyde dehydrogenase, as well as unknown transcripts (three clones), and the human homologues of the molecular motor kinesin KIF3B and of the ser/thr protein kinase EMK1. Spot dot and Northern blot analyses showed that ser/thr protein kinase EMK1 was differentially expressed in M6 cells when compared with parental HT-29 cells. Steady-state levels of EMK1 were higher in proliferating, preconfluent, M6 and HT-29 cells than in 2 days post confluence (dpc) and 8dpc M6 and HT-29 cells. Transcripts that included an Alu repeat were also shown to be differentially expressed and accumulated in differentiating M6 cells when analysed by Northern blot. The significance of the transcripts cloned is discussed in the context of the commitment and differentiation of the M6 cells to the mucus secreting lineage of epithelial cells.
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PMID:Expressed sequence tag (EST) phenotyping of HT-29 cells: cloning of ser/thr protein kinase EMK1, kinesin KIF3B, and of transcripts that include Alu repeated elements. 1039 37

The synthetic flavone flavopiridol can be cytostatic or cytotoxic to mammalian cells, depending on the concentration of the drug and the duration of exposure. It has been shown to inhibit the cyclin-dependent kinase (CDK) family of cell cycle regulatory enzymes. However, the existence of additional potential targets for drug action remains a matter of interest to define. To identify cellular targets, flavopiridol was immobilized. CDKs, particularly CDK 4, bound weakly to immobilized flavopiridol when ATP was absent but not in its presence. Two proteins with molecular weights of 40 kDa and 120 kDa had high affinities to the immobilized flavopiridol independent of the presence of ATP. They were present in all cell lines analyzed: cervical (HeLa), prostate and non-small cell lung carcinoma (NSCLC) cell lines. A 60-kDa protein, which was present only in NSCLC cells and bound similarly well to immobilized flavopiridol, was identified as cytosolic aldehyde dehydrogenase class 1 (ALDH-1). The level of this protein correlated with the resistance of NSCLC cell lines to cytotoxicity caused by 500 nM flavopiridol but not higher flavopiridol concentrations. Despite binding to ALDH-1, there was no inhibition of dehydrogenase activity by flavopiridol concentrations as high as 20 microM and flavopiridol was not metabolized by ALDH-1. The results suggest that high cellular levels of ALDH-1 may reduce cytotoxicity of flavopiridol and contribute to relative resistance to the drug. This is the first report that flavopiridol binds to proteins other than CDKs.
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PMID:Identification of cytosolic aldehyde dehydrogenase 1 from non-small cell lung carcinomas as a flavopiridol-binding protein. 1041 4

This review focuses on the clinical development of the prototype broad spectrum inhibitor of cyclin-dependent kinases (CDKs), flavopiridol, now undergoing Phase II single-agent trials and Phase I combination trials (with paclitaxel and cisplatin). Preclinically, flavopiridol is a potent inhibitor of CDKs 1, 2 and 4 in cell-free assays (IC(50)in the region of 100 nM) and tumour cell growth in vitro (typical IC(50)in the region of 100 nM). The drug showed in vivo antitumour activity (using iv., ip. or oral dosing) against a variety of human tumour xenografts, especially when administered on a regular daily, rather than weekly, schedule and most notably against prostate carcinoma, head and neck cancer, non-Hodgkin's lymphoma and leukaemia. The major toxicities observed in rodents were on the bone marrow and gastrointestinal tract. Pharmacokinetics were linear with dose and with a bi-exponential decline both in rodents and man. Oral bioavailability in rodents is in the region of 20%. Glucuronidation appears to be the major route of metabolism. Single-agent clinical trials have mainly used a 72 h continuous infusion schedule. Dose-limiting toxicities were diarrhoea and hypotension. Plasma concentrations in excess of those required for in vitro enzyme or cell growth inhibition are achievable. While there has been some evidence of single-agent antitumour activity (partial responses in a patient with renal cancer and another with gastric cancer), ongoing combination studies, especially with paclitaxel, where preclinical synergistic antitumour effects are observed, are promising. Doubt as to whether CDKs are the sole target responsible for the drug's antitumour effects have been raised by preclinical observations of apoptosis of non-cycling cells, effects on endothelial cells and non-CDK proteins, such as aldehyde dehydrogenase and glycogen phosphorylase, potent effects on PTEFb and transcription and its ability to directly interact with DNA.
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PMID:Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. 1109 60

Mice with a fat-specific insulin receptor knock-out (FIRKO) have reduced adipose tissue mass, are protected against obesity, and have an extended life span. White adipose tissue of FIRKO mice is also characterized by a polarization into two major populations of adipocytes, one small (<50 microm) and one large (>100 microm), which differ with regard to basal triglyceride synthesis and lipolysis, as well as in the expression of fatty acid synthase, sterol regulatory element-binding protein 1c, and CCAAT/enhancer-binding protein alpha (C/EBP-alpha). Gene expression analysis using RNA isolated from large and small adipocytes of FIRKO and control (IR lox/lox) mice was performed on oligonucleotide microarrays. Of the 12,488 genes/expressed sequence tags represented, 111 genes were expressed differentially in the four populations of adipocytes at the p < 0.001 level. These alterations exhibited 10 defined patterns and occurred in response to two distinct regulatory effects. 63 genes were identified as changed in expression depending primarily upon adipocyte size, including C/EBP-alpha, C/EBP-delta, superoxide dismutase 3, and the platelet-derived growth factor receptor. 48 genes were regulated primarily by impairment of insulin signaling, including transforming growth factor beta, interferon gamma, insulin-like growth factor I receptor, activating transcription factor 3, aldehyde dehydrogenase 2, and protein kinase Cdelta. These data suggest an intrinsic heterogeneity of adipocytes with differences in gene expression related to adipocyte size and insulin signaling.
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PMID:Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knock-out mice is associated with differences in patterns of gene expression. 1513 Nov 19


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