Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cisplatin is one of the most widely used chemotherapeutic agents. However, at sublethal concentrations, resistance of cells to the drug occasionally arise, which greatly limits its effectiveness in cancer therapy. In this review, the mechanisms of acquired resistance to cisplatin are elucidated. Numerous mechanisms potentially contributing to clinical cisplatin resistance have been identified, including changes in membrane permeability, detoxification pathways and the ability to remove cytotoxic lesions from DNA. Changes triggered by cisplatin selection in the resistant phenotype involve a secondary layer of complexity that may include alterations in: 1) oncogene and protein kinase signal transduction pathways: 2) growth factor and hormone responsiveness; 3) chromosome structure and gene expression; 4) ion transport; 5) thymidilate metabolism; and 6) nutrient transport and utilization. It is likely that all of these changes are part of an interconnected, multifarious response to cisplatin selection. Which of these biochemical changes come to predominate may depend on the type of cell and, particularly, on the selection procedure. In general, chronic, long-term exposure to increasing concentrations of cisplatin seems to lead to permanent elevations in the levels of the nucleophiles glutathione and metallothionein. Pulsed administration of cisplatin once a week leads to changes in folate metabolism and oncogene expression, while acute administration of cisplatin once a month leads to defects in drug accumulation. However, the environment of a tumor is remarkably different from the environment of tumor cells in culture (nutrient, growth factor and hormone availability; pH; intercellular communication; and oxygenation state). In addition, the various oncogene and protein kinase signal transduction pathways are likely to be featured differently in these two environments. In contrast to the sublethal concentrations of cisplatin used in the selection of resistance phenotype a lethal concentration of cisplatin may generate DNA adducts in cells, which cause G2 arrest of the cell cycle and subsequently lead to apoptosis. Recently, excitement in this field arose from the findings that cisplatin-DNA adducts bind several cellular proteins, termed cisplatin-damaged-DNA recognition proteins, including some that enhance survival of the cells by mediating DNA repair and others that hasten their death by conferring sensitivity to the drug.
 ...
PMID:Molecular basis of cis-diamminedichloroplatinum(II) resistance: a review. 900 Aug 4

RN46A cells, a conditionally immortalized neuronal cell line derived from E12 rat medullary raphe nucleus, upregulate low M(r) (68 kDa, neurofilament [NF]-L) and medium M(r) (160 kDa, NF-M) neurofilament protein expression upon activation of protein kinase A (PKA). To examine possible transcriptional regulation of neurofilament protein expression by PKA, two cell lines were used; RN46A cells and C alpha EV6 cells, a cell line derived from RN46A cells that stably expresses the catalytic subunit of PKA under the control of the metallothionein promoter. Treatment of RN46A cells with dbcAMP resulted in an increase in the steady-state levels of both NF-L and NF-M, but not high M(r) (200 kDa, NF-H) neurofilament mRNA. These increases were both time and dose dependent and were sensitive to treatment with the protein synthesis inhibitor cycloheximide. In C alpha EV6 cells, activation of PKA by 80 microM ZnSO4 upregulated the expression of C alpha mRNA with maximal levels reached 8 hr post-treatment and maintained at 24 hr. Reporter gene assays in C alpha EV6 cells following transfection with increasing lengths of the NF-L promoter demonstrated that both a putative Sp1-like and a cAMP response (CRE), but not a NGFI-A, element were likely involved in PKA-dependent activation of the NF-L promoter. Electrophoretic mobility shift assays confirmed these results but showed that the nuclear proteins induced by PKA which bound to the NF-L promoter Sp1-like sequence were not Sp1. Collectively, these data suggest that constitutively expressed Sp1 may be involved in basal NF-L promoter activity, and newly synthesized, PKA-dependent nuclear proteins may synergistically activate the rat NF-L promoter.
 ...
PMID:Transcriptional regulation of neurofilament expression by protein kinase A. 903 46

The effects of protein kinase C (PKC) inhibitors on the metallothionein (MT) gene expression induced by metals were investigated. When PKC inhibitor (H7 or chelerythrine) was administered to Cd resistant, MT gene-amplified Chinese hamster ovary (CdR) cells, the induction of MT mRNA by Cd or Zn was blocked. Treating the CdR cells with a PKA-specific inhibitor, HA1004, did not cause an inhibition of metal-induced MT gene transcription. The inhibitory effect was effectuated by adding inhibitors within 40 min of exposing the cells to Cd. Apparently, AP1 was not involved in this down-regulatory effect of PKC inhibitor on MT gene expression since the inducibility of MT promoter was blocked by H7 even in the absence of the AP1-binding sequence. For Cd-treated cells, Cd accumulation in the cell was similar with or without H7 treatment. However, H7 markedly reduced cellular Zn accumulation when the cells were treated with Zn. Cycloheximide treatment increased the level of MT mRNA. This elevation can also be blocked by treating the cell with PKC inhibitor. Results in this study suggest that PKC participates in the process of metal-induced MT gene expression.
 ...
PMID:Metal-induced metallothionein gene expression can be inactivated by protein kinase C inhibitor. 945 May 52

The cAMP-dependent pathway has been long presumed to play a critical role in mediating alpha-melanocyte-stimulating hormone (alpha-MSH)-induced pigmentation, but it has never been demonstrated that this pathway is obligatory. In order to determine whether the cAMP-dependent pathway is required for a alpha-MSH-induced pigmentation, we inhibited the activity of cAMP-dependent protein kinase (PKA), the main kinase mediating in this pathway, by introducing a physiologic cAMP-dependent protein kinase inhibitor (PKI) into S91 murine melanoma cells and then measuring pigment response after alpha-MSH stimulation. Cells were stably transfected either with the pMXX-PKI expression vector that encodes the active part of PKI (the amino terminal 1-31 amino acids) under a metallothionein-inducible promoter and the pSV2-Neo expression vector alone. As expected, treatment of transfected cells with 1 microM CdCl2 for 24 h induced the expression of PKI mRNA in cells transfected with both vectors, but not in cells transfected with the pSV2-Neo expression vector alone. Subsequent treatment of these transfected cells with alpha-MSH for 5-6 days in the continual presence of 1 microM CdCl2 resulted in inhibition of PKA activity by 30-40% in cells expressing PKI. Parallel measurements revealed that alpha-MSH-increased melanin content five- to six-fold in control cells transfected with pSV2-Neo alone, while there was only a two-fold increase in PKI-expressing cells, a 40-50% inhibition in alpha-MSH-induced total melanin content. alpha-MSH-induced tyrosinase activity and tyrosinase mRNA and protein levels measured in parallel were also inhibited by 40-50% in PKI-expressing cells compared to control cells transfected with pSV2-Neo alone. Together, these results demonstrate for the first time that activation of PKA through the cAMP-dependent pathway is required for optimal alpha-MSH-induced pigmentation.
 ...
PMID:Activation of cAMP-dependent protein kinase is required for optimal alpha-melanocyte-stimulating hormone-induced pigmentation. 977 Mar 55

The transition metal cadmium is a pervasive and persistent environmental contaminant that has been shown to be both a human toxicant and carcinogen. To inhibit cadmium-induced damage, cells respond by increasing the expression of genes encoding stress-response proteins. In most cases, the mechanism by which cadmium affects the expression of these genes remains unknown. It has been demonstrated in several instances that cadmium activates gene transcription through signal transduction pathways, mediated by protein kinase C, cAMP-dependent protein kinase, or calmodulin. A codicil is that cadmium should influence the expression of numerous genes. To investigate the ability of cadmium to affect gene transcription, the differential display technique was used to analyze gene expression in the nematode Caenorhabditis elegans. Forty-nine cDNAs whose steady-state levels of expression change 2-6-fold in response to cadmium exposure were identified. The nucleotide sequences of the majority of the differentially expressed cDNAs are identical to those of C. elegans cosmids, yeast artificial chromosomes, expressed sequence tags, or predicted genes. The translated amino acid sequences of several clones are identical to C. elegans metallothionein-1, HSP70, collagens, and rRNAs. In addition, C. elegans homologues of pyruvate carboxylase, DNA gyrase, beta-adrenergic receptor kinase, and human hypothetical protein KIAA0174 were identified. The translated amino acid sequences of the remaining differentially expressed cDNAs encode novel proteins.
 ...
PMID:Cadmium-regulated genes from the nematode Caenorhabditis elegans. Identification and cloning of new cadmium-responsive genes by differential display. 982 67

The basic region/helix-loop-helix/leucine zipper (B-HLH-LZ) oncoprotein c-Myc is abundant in proliferating cells and forms heterodimers with Max protein that bind to E-box sites in DNA and stimulate genes required for proliferation. A second B-HLH-LZ protein, Mxi1, is induced during terminal differentiation, and forms heterodimers with Max that also bind E-boxes but tether the mSin3 transcriptional repressor protein along with histone deacetylase thereby antagonizing Myc-dependent activation. We show that Mxi1 also antagonizes Myc by a second pathway, repression of transcription from the major c-myc promoter, P2. Repression was independent of Mxi1 binding to mSin3 but dependent on the Mxi1 LZ and COOH-terminal sequences, including putative casein kinase II phosphorylation sites. Repression targeted elements of the myc P2 promoter core (-35/+10), where it reversed transactivation by the constitutive transcription factor, USF. We show that Zn2+ induction of a stably transfected, metallothionein promoter-regulated mxi1 gene blocked the ability of serum to induce transcription of the endogenous c-myc gene and cell entry into S phase. Thus, induction of Mxi1 in terminally differentiating cells may block Myc function by repressing the c-myc gene P2 promoter, as well as by antagonizing Myc-dependent transactivation through E-boxes.
 ...
PMID:Mxi1 is a repressor of the c-Myc promoter and reverses activation by USF. 987 93

Cells from patients with the human genetic disorder ataxia-telangiectasia (A-T) are defective in the activation of cell cycle checkpoints in response to ionizing radiation damage. In order to understand the role of ATM in checkpoint control we investigated whether Schizosaccaromyces pombe chk1, a protein kinase implicated in controlling the G2 DNA damage checkpoint, might alter the radiosensitive phenotype in A-T cells. The fission yeast chkl gene was cloned into an EBV-based vector under the control of a metallothionein promoter and transfected into A-T lymphoblastoid cells. Induction of chk1 enhanced the survival of an A-T cell line in response to radiation exposure as determined by cell viability and reduction of radiation-induced chromosome aberrations. This can be accounted for at least in part by the restoration of the G2 checkpoint to chk1 expressing cells. There was no evidence that chk1 expression corrected either the G1/S checkpoint or radioresistant DNA synthesis in S phase in these cells. These results suggest that chk1 when overexpressed acts downstream from ATM to restore the G2 checkpoint in these cells and correct the radiosensitive phenotype. These data allow us to dissociate individual checkpoint events and relate them to the radiosensitive phenotype in A-T cells.
 ...
PMID:Chk1 complements the G2/M checkpoint defect and radiosensitivity of ataxia-telangiectasia cells. 992 40

The involvement of the double-stranded RNA-activated protein kinase PKR in the regulation of the myogenic process was investigated. For this purpose, the murine myogenic cell line C2C12 was used. The cells were first cultivated in either growth medium or differentiation medium (DM), and the activation of PKR during differentiation was determined by monitoring its enzymatic activity and by immunoblot analysis. A significant increase in both parameters was detected already at 24 h in DM, whereas in cells grown in growth medium, the increase was evident only after 96 h, when spontaneous differentiation was observed in highly crowded cultures. Consequently, we established the direct effect of PKR activation on the myogenic process. C2C12 cells were transfected with an expression vector harboring a cDNA molecule encoding human PKR fused to the inducible metallothionein promoter. One of the clones (clone 8) expressing high levels of PKR was selected and further analyzed. In the presence of ZnCl2, which activates the promoter, the rate of cell growth of the transfected cells was clearly reduced compared to that of wild-type C2C12 cells transfected with only the neomycin-resistant gene (C2-NEO). In addition, altered morphology with partial fusion was observed. Biochemically, an increase in creatine kinase activity accompanied by an increased rate of expression of the myogenic protein troponin T and the myogenic transcription factors myoD and myogenin was detected in clone 8 cells exposed to ZnCl2. Most importantly, an induction in the level of cyclin-dependent kinase inhibitor p21WAF1 and an increase in the level of the underphosphorylated active form of the tumor suppressor protein pRb concomitant with the down-regulation of cyclin D1 and c-myc were also evident in the transfected clones. These changes were similar to those observed in normal C2C12 cells cultivated in DM. We conclude that PKR is an important regulatory protein participating in the myogenic process.
 ...
PMID:Involvement of PKR in the regulation of myogenesis. 1009 34

cAMP-dependent protein kinase (cAK) regulates the activity of several membrane-bound ion channels and carriers. The role of cAK in regulating the transport of osmoprotective amino acids in the distal tubule is unknown. We examined the regulation of Na(+)- and Cl(-)-dependent proline transport in MDCK cells expressing a mutant murine regulatory subunit (RIalpha(AB)) of cAK. For this purpose, MDCK cells were transfected with an expression vector encoding RIalpha(AB) driven by the metallothionein 1 promoter together with neomycin-resistance (NEO) gene. Stable G418-resistant colonies were isolated that expressed RIalpha(AB) as demonstrated by Northern hybridization analysis using a cDNA probe for RIalpha and cAK assay that showed decreased enzyme activity. A clone constitutively expressing high levels of RIalpha(AB) (M(AB)) in a Zn-independent manner and a control clone transfected with the NEO gene alone (M(neo)) were selected for transport studies. We examined the effect of the cAMP-stimulating agents forskolin (F) and IBMX on NaCl-dependent uptake of [(3)H]proline by confluent monolayers of transfected MDCK cells. While F/IBMX-induced mean inhibition of proline transport in M(neo) cells was 48 and 45% at 5 and 15 min, respectively, inhibition of proline uptake in M(AB) cells was 9% (5 min) and 0% (15 min). These data demonstrate that the inhibition of NaCl-linked proline transport in response to elevated cAMP is reversed in MDCK clones that express mutant cAK and provide evidence that cAK mediates the modulatory action of cAMP on proline transport. cAK may play an important role in controlling transport of proline and other osmoprotective amino acids in the renal tubule.
 ...
PMID:Proline transport in MDCK cells expressing a mutant regulatory subunit of cAMP-dependent protein kinase. 1116 28

We have studied the role of phosphorylation in the activation of metal-regulatory transcription factor-1 (MTF-1) and metallothionein (MT) gene expression. We showed that MTF-1 is phosphorylated in vivo and that zinc stimulates MTF-1 phosphorylation 2-4-fold. Several kinase inhibitors were used to examine the possible involvement of kinase cascades in the activation of MTF-1. Metal-induced MT gene expression was abrogated by protein kinase C (PKC), c-Jun N-terminal kinase (JNK), phosphoinositide 3-kinase, and tyrosine-specific protein kinases inhibitors, as assayed by Northern analysis and by cotransfection experiments using a metal regulatory element-luciferase reporter plasmid. The extracellular signal-activated protein kinase and the p38 kinase cascades did not appear to be essential for the activation of MT gene transcription by metals. By using dominant-negative mutants of PKC, JNK, mitogen-activated kinase kinase 4 (MKK4), and MKK7, we provide further evidence supporting a role for PKC and JNK in the activation of MTF-1 in response to metals. Notably, increased MTF-1 DNA binding in response to zinc and MTF-1 nuclear localization was not inhibited in cells preincubated with the different kinase inhibitors despite strong inhibition of MTF-1-mediated gene expression. This suggests that phosphorylation is essential for MTF-1 transactivation function. We hypothesize that metal-induced phosphorylation of MTF-1 is one of the primary events leading to increased MTF-1 activity. Thus, metal ions such as cadmium could activate MTF-1 and induce MT gene expression by stimulating one or several kinases in the MTF-1 signal transduction pathway.
 ...
PMID:Phosphorylation is involved in the activation of metal-regulatory transcription factor 1 in response to metal ions. 1155 72


<< Previous 1 2 3 4 5 6 Next >>