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)

Zinc is essential for cell proliferation and differentiation, especially for the regulation of DNA synthesis and mitosis. On the molecular level, it is a structural constituent of a great number of proteins, including enzymes of cellular signaling pathways and transcription factors. Zinc homeostasis in eukaryotic cells is controlled on the levels of uptake, intracellular sequestration in zinc storing vesicles ('zincosomes'), nucleocytoplasmic distribution and elimination. These processes involve the major zinc binding protein metallothionein as a tool for the regulation of the cellular zinc level and the nuclear translocation of zinc in the course of the cell cycle and differentiation. In addition, there is also increasing evidence for a direct signaling function for zinc on all levels of signal transduction. Zinc can modulate cellular signal recognition, second messenger metabolism, protein kinase and protein phosphatase activities, and it may stimulate or inhibit activities of transcription factors, depending on the experimental systems studied. Zinc has been shown to modify specifically the metabolism of cGMP, the activities of protein kinase C and mitogen activated protein kinases, and the activity of transcription factor MTF-1 which controls the transcription of the genes for metallothionein and the zinc transporter ZnT-1. As a conclusion of these observations new hypotheses regarding regulatory functions of zinc ions in cellular signaling pathways are proposed.
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PMID:Functions of zinc in signaling, proliferation and differentiation of mammalian cells. 1183 63

Every living organism must detoxify nonessential metals and carefully control the intracellular concentration of essential metals. Metallothioneins, which are small, cysteine-rich, metal-binding proteins, play an important role in these processes. In addition, the transcription of their cognate genes is activated in response to metal exposure. The zinc finger transcription factor MTF-1 plays a central role in the metal-inducible transcriptional activation of metallothionein and other genes involved in metal homeostasis and cellular stress response. Here we report that the phosphorylation of MTF-1 plays a critical role in its activation by zinc and cadmium. Inhibitor studies indicate that multiple kinases and signal transduction cascades, including those mediated by protein kinase C, tyrosine kinase, and casein kinase II, are essential for zinc- and cadmium-inducible transcriptional activation. In addition, calcium signaling is also involved in regulating metal-activated transcription. In contrast, cAMP-dependent protein kinase may not be directly involved in the metal response. Contrary to what has been reported for other transcription factors, inhibition of transcriptional activation does not impair the binding of MTF-1 to DNA, suggesting that phosphorylation is not regulating DNA binding. Elevated phosphorylation of MTF-1 is observed under condition of protein kinase C inhibition, suggesting that specific dephosphorylation of this transcription factor contributes to its activation.
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PMID:Regulation of metallothionein transcription by the metal-responsive transcription factor MTF-1: identification of signal transduction cascades that control metal-inducible transcription. 1192 82

Advances in molecular and cell biology have led to further understanding of the mechanisms of malignant growth and metastasis in human breast cancer cells. Initiation and progression of breast cancer results from mutations and the abnormal expression of many genes that control cellular proliferation, differentiation, invasion, metastasis and sensitivity to therapy (chemotherapy and radiation therapy). Inhibition of host immunity also plays a role in breast cancer progression. Many genes have been selected as targets for antisense therapy, including HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, BRCA, Bcl-2, ER, VEGF, MDR, ferritin, transferrin receptor, IRE, C-fos, HSP27, C-myc, C-raf and metallothionein genes. The strategy behind antisense therapy is the development of specific therapeutic agents that aim to correct the mutations and abnormal expression of cellular genes in breast tumour cells by decreasing gene expression, inducing degradation of target mRNA and causing premature termination of transcription. Many in vitro and in vivo studies have investigated the therapeutic efficacy of oligonucleotides and antisense RNAs. These studies have demonstrated specific inhibition of tumour cell growth by antisense therapy and have shown synergistic inhibitory effects between antisense oligonucleotides or antisense RNA and conventional chemotherapeutic drugs used in the treatment of breast cancer. Antisense oligonucleotides have been modified to improve their ability to penetrate cells, bind to gene sequences and downregulate target gene function. Many delivery systems for antisense RNA and antisense oligonucleotides have been developed, including virus vectors (retrovirus, adenovirus and adeno-associate virus) and liposomes, to carry the antisense RNA or oligonucleotides through the cell membrane into the cytoplasm and nucleus of the tumour cells. However, in order to determine their feasibility antisense therapies need to be further investigated to determine their antitumour activity, pharmacokinetics and toxicity in breast cancer patients.
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PMID:Gene targets of antisense therapies in breast cancer. 1222 74

Metallothioneins are small, cysteine-rich, metal-binding proteins that play important roles in maintaining intracellular metal homeostasis and in transition metal detoxification. MTF-1 (metal transcription factor-1) plays a central role in regulating the metal-inducible, transcriptional activation of metallothionein. Here we report that the phosphorylation of MTF-1 plays a critical role in the activation of MTF-1/metal-responsive element-mediated transcription. Inhibitor studies indicate that signal transduction cascades, including those mediated by protein kinase C, tyrosine kinase, and casein kinase II, are essential for zinc- and cadmium-inducible transcription. In addition, calcium signaling is also involved in regulating transcription. In contrast, cAMP-dependent protein kinase may not be directly involved in the metal response. Contrary to what has been reported for other transcription factors, the inhibition of transcriptional activation does not impair the binding of MTF-1 to DNA, suggesting that phosphorylation is not regulating DNA binding. Elevated phosphorylation of MTF-1 is observed under conditions of protein kinase C inhibition, suggesting that dephosphorylation of this transcription factor mediates its activation.
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PMID:Activation of gene expression by metal-responsive signal transduction pathways. 1242 37

Elemental mercury (Hg0) is a highly toxic chemical with increasing public health concern. Although the lung receives the highest exposure to Hg0 vapor, it is resistant to Hg0 toxicity relative to the kidney and brain. In an earlier study, exposure of rats to 4 mg Hg0 vapor/m3, 2 h per day for 10 days, did not produce pathological alterations in the lung but increased metallothionein and glutathione S-transferase in the kidney. This study was undertaken to examine pulmonary gene expression associated with Hg0 vapor inhalation. Total RNA was extracted from lung tissues of rats, previously exposed to air or Hg0 vapor, and subjected to microarray analysis. Hg0 vapor exposure increased the expression of genes encoding inflammatory responses, such as chemokines, tumor necrosis factor-alpha (TNFalpha), TNF-receptor-1, interleukin-2 (IL-2), IL-7, prostaglandin E2 receptor, and heat-shock proteins. As adaptive responses, glutathione S-transferases (GST-pi, mGST1), metallothionein, and thioredoxin peroxidase were all increased in response to Hg exposure. Some transporters, such as multidrug resistance-associated protein (MRP), P-glycoprotein, and zinc transporter ZnT1, were also increased in an attempt to reduce pulmonary Hg load. The expression of transcription factor c-jun/AP-1 and PI3-kinases was suppressed, while the expression of protein kinase-C was increased. Expression of epidermal fatty acid-binding protein was also enhanced. Real-time RT-PCR and Western blot analyses confirmed the microarray results. In summary, genomic analysis revealed an array of gene alterations in response to Hg0 vapor exposure, which could be important for the development of pulmonary adaptation to Hg during Hg0 vapor inhalation.
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PMID:Genomic analysis of the rat lung following elemental mercury vapor exposure. 1273 Jun 25

Isoflavone, genistein, was shown to have antioxidant and antitumor activities. We have reported the stimulatory effect of genistein on the expression of antioxidant and metal-binding protein, metallothionein IIA (MTIIA), in human intestinal Caco-2 cells. Genistein has been shown to up-regulate the expression of other genes through estrogen response element (ERE) but the ERE sequence is not in the MTIIA promoter. In this paper, we investigated the ERE-independent mechanism that mediates the stimulatory effect of genistein. Genistein enhanced the expression of human MTIIA promoter (up to -426)-containing reporter genes, thus supporting a promoter-specific transcriptional regulation. A shorter MTIIA promoter (-83 to +27) was found to be able to mediate the full reporter gene response to genistein in a dose- and time-dependent fashion. Further deletion and mutation analysis revealed that the GC-rich Sp1 binding sequence was the target of the stimulation. Genistein was known to bind to estrogen receptors (ER). When cells were cotransfected with ER beta, the stimulatory effect of genistein on the reporter gene containing the GC-rich promoter sequence increased further and a similar result was observed for breast cancer MCF-7 cells. Inhibitors of protein kinase A could block the response to genistein but the phosphorylation of Sp1 protein per se was not affected by the genistein treatment. Our observation could help to evaluate the biological significance of genistein, which is used widely as a supplement.
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PMID:Estrogen response element-independent regulation of gene expression by genistein in intestinal cells. 1281 23

Post-translational modification of MTF-1 (metal-response-element-binding transcription factor-1) was suggested to play a role in its metalloregulatory functions. In the present study, pulse labelling and two-dimensional electrophoresis-Western blotting were used to demonstrate that, although MTF-1 is highly modified in vivo, its phosphorylation level does not rapidly change in response to metals, nor does its overall modification pattern. Recombinant MTF-1 was found to serve as an in vitro substrate for casein kinase II, c-Jun N-terminal kinase and protein kinase C, but inhibition of these kinases in vivo did not significantly change the modification pattern of MTF-1. Northern blotting revealed that inhibitors of casein kinase II and c-Jun N-terminal kinase severely attenuate the metal-induced transcription of the native chromatin-packaged metallothionein-I and zinc transporter-1 genes, whereas protein kinase C inhibitors exerted gene- and cell-type-specific effects on the metal regulation and basal expression of these two genes. A chromatin immunoprecipitation assay was used to demonstrate that none of these inhibitors prevent the metal-dependent recruitment of MTF-1 to the MT-I promoter. In brief, results of the present study suggest that protein kinases may not alter the phosphorylation state of MTF-1 during the rapid-response phase to metals, nor do they regulate the metal-dependent formation of a stable MTF-1-chromatin complex. Instead, protein kinases may exert their interdependent effects on metal-induced gene expression by acting on cofactors that interact with MTF-1.
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PMID:Gene- and cell-type-specific effects of signal transduction cascades on metal-regulated gene transcription appear to be independent of changes in the phosphorylation of metal-response-element-binding transcription factor-1. 1514 38

The molecular mechanism of sulforaphane on the induction of metallothionein (MT) genes in HepG2 cells and the antiproliferative effects of sulforaphane were investigated in this study. Treatment of the cells with sulforaphane at non-toxicity concentration (0-20 microM) resulted in coordinate increases in the induction of MT-I and MT-II mRNA, followed by corresponding increases in MT protein expression. Western blot analysis revealed the increased level of the transcription factor, Nrf2 in a time-dependent manner from sulforaphane-treated cells. Furthermore, sulforaphane activated the extracellular signal-regulated protein kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways. SB203580, a specific inhibitor of p38 and PD98059, a specific inhibitor of ERK, abolished sulforaphane-induced MT protein expression, whereas SP600125, a specific inhibitor of JNK, had no significant effect. At relatively high concentration (30-100 microM), sulforaphane is a cell growth modulator, as it induced apoptotic cell death characterized by internucleosomal DNA fragmentation and caused a rapid induction of caspase 3 activity, according to the appearance of the caspase 3 fragments and stimulated proteolytic cleavage of poly (ADP-ribose) polymerase in a time-dependent manner. Moreover, sulforaphane-induced apoptotic cell death was accompanied by upregulation of Bax and downregulation of Bcl-2 and Bcl-X(l) protein. Sulforaphane-induced DNA fragmentation was blocked by the N-acetyl-L-cysteine and catalase, suggesting that the death signaling was triggered by oxidative stress. Taken together these results strongly suggest that at low concentrations of sulforaphane, activation of MAPKs, such as ERK and p38 pathway, lead to Nrf2-mediated MT gene expression. Whereas at a higher concentration, sulforaphane is an effective apoptosis inducer in HepG(2) cells through regulation of Bcl-2 family molecular and activation of ICE/Ced-3 protease (caspase 3) cascade. The results from this study may provide more evidence for its chemopreventive function.
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PMID:Effect of sulforaphane on metallothionein expression and induction of apoptosis in human hepatoma HepG2 cells. 2431 95

Recently, we discovered that beta-thujaplicin (BT) induces metallothionein (MT) expression in mouse keratinocytes, both in vivo and in vitro. However, the molecular mechanisms by which BT exerts its biological effects have not been elucidated. The purpose of this study is to explore the signal transduction pathway involved in the MT mRNA induction by BT. Using a HaCaT keratinocyte cell line, Northern blotting was performed for analyzing the human MT-IIA mRNA expression levels in combination with BT and a number of protein kinase (PK) inhibitors including H7, HA1004 and a PKC-specific inhibitor chelerythrin. CAT assays with the MT-IIA gene promorter-CAT construct were conducted for examining the transcriptional regulation by BT of MT. A free radical scavenger N-acetylcysteine (NAC) was used for analyzing a role of oxidative stress for the MT gene induction by BT. BT increased MT-IIA gene transcript levels and CAT activity in a dose-dependent fashion in HaCaT cells. The increase in MT-IIA mRNA levels and CAT activity were completely suppressed by H7 but not by HA1004. In addition, chelerythrin prevented BT-inducible MT-IIA promoter activation. Furthermore, NAC suppressed BT-inducible MT-IIA promoter activation. These results demonstrate that BT is a potent activator of the MT-IIA gene promoter and that PKC activation and reactive oxygen species are implicated in BT-inducible MT-IIA gene expression. BT may be a useful tool for dissecting the signal transduction pathway mediating MT-IIA promoter activation.
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PMID:Human metallothionein gene expression is upregulated by beta-thujaplicin: possible involvement of protein kinase C and reactive oxygen species. 1639 9

Esophageal squamous cell carcinoma (ESCC) in the Indian population is associated with poor nutritional status, low socioeconomic conditions, bidi smoking and consumption of smokeless tobacco products, besides alcohol drinking and cigarette smoking. To determine the impact of these risk factors on molecular pathogenesis of ESCC, we determined global gene expression profiles of 7 paired samples of ESCC and histologically confirmed nonmalignant esophageal tissues using 19.1K cDNA microarrays. The most salient finding was identification of 19 differentially expressed genes encoding zinc binding or modulating proteins associated with transcriptional regulation, ubiquitin-protein degradation and maintenance of zinc homeostasis. Validation of differential expression of a subset of genes by real-time quantitative RT-PCR (real-time QRT-PCR) in clinical specimens of ESCC, esophageal dysplasia and histologically nonmalignant esophageal tissues and immunohistochemical analysis using tissue microarrays confirmed the microarray data and demonstrated upregulation of zinc finger proteins, cellular modulator of immune recognition (c-MIR), snail homolog 2 (SLUG), zinc transporter, ZnT7 and downregulation of zinc metabolizing protein, metallothionein MT1G. We also observed upregulation of mitogen activated protein kinase kinase kinase 3 (MAP3K3/MEKK3), a kinase anchor protein 13 (AKAP13) and transglutaminase2 (TG2). Interestingly, we found upregulation of ZnT7 transcripts in ESCC cells (TE13) grown in zinc deficient condition. In conclusion, our data suggest deregulation of genes associated with zinc homeostasis in ESCC.
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PMID:Discovery of deregulation of zinc homeostasis and its associated genes in esophageal squamous cell carcinoma using cDNA microarray. 1706 19


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