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)

The WAF1/Cip1 protein is an important regulator at the G1 checkpoint in the cell cycle. The WAF1/Cip1 protein binds to the cyclin-dependent kinase complexes and inhibits the kinase activity that is required for cell cycle progression. We investigated the expression of WAF1/Cip1 protein in 14 glioblastoma cell lines and found that WAF1/Cip1 expression was detectable in many of the cell lines, even when mutant p53 was present. We also showed that WAF1/Cip1 protein level was very low in LN-Z308 cells that do not express endogenous p53. Transfection of the wild-type p53 into this cell line activated WAF1/Cip1 expression and inhibited cell growth. In contrast, transfection of the p53 mutant 248Trp failed to activate WAF1/Cip1 expression. Transfection of WAF1/Cip1 alone also inhibited LN-Z308 cell proliferation. However, cotransfection of the p53 mutant 248Trp with WAF1/Cip1 attenuated the growth-suppression effect of WAF1/Cip1. Our analysis with Western blot showed that the levels of cyclin E increased in cells transfected with p53 mutants. We conclude that p53 mutants may counter the negative regulators, such as WAF1/Cip1, by the elevation of positive cell cycle regulators, and the presence of WAF1/Cip1 in tumor cells is not sufficient for growth inhibition.
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PMID:Inhibition of human glioblastoma cell growth by WAF1/Cip1 can be attenuated by mutant p53. 854 19

The creatine kinase isoenzymes play an important role in maintaining ATP levels in some cell types during times of high energy demand. We have previously shown in primary cell cultures from rat brain that glial cells express much higher levels of brain creatine kinase (CKB) mRNA than neurons. In a separate earlier study we observed that transcription of CKB mRNA in glial cells can be stimulated by a forskolin-mediated increase in cAMP via a pathway involving protein kinase A (PKA). In this report, we show that the level of CKB mRNA in human U87 glioblastoma cells can be increased by either prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), or cholera toxin (an activator of G alpha s proteins). The induction of CKB mRNA occurs rapidly (with maximal induction after 6 h), is at the level of transcription, and is mediated specifically through PKA. In addition, the results indicate that both PGE1 and PGE2 use the same or related signal transduction pathways to increase CKB transcription. These results suggest that in glial cells CKB mRNA can be regulated by extracellular signals acting through G-protein-coupled receptors. This study may contribute to an understanding of the mechanisms underlying the previously-reported, early postnatal increase in CKB enzyme activity in rat brain. The results are also discussed with regard to the potential involvement of the expression of prostaglandins and CKB during hypoxia and ischemia.
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PMID:Prostaglandin E1, E2, and cholera toxin increase transcription of the brain creatine kinase gene in human U87 glioblastoma cells. 892 40

Previously these authors and others demonstrated frequent homozygous deletions of the chromosome 9p-localized class I interferon (IFN) gene cluster in glioblastoma tumors and cell lines. To investigate the biological effects of class I IFN gene transfer and constitutive expression in glioblastoma cells devoid of this gene cluster, the authors have developed a stable IFNalpha "transfectant" of the cell line U118. The expression of IFNalpha protein in the U118 transfectant clone is associated with decreased levels of DNA synthesis exhibited by cultures of transfected cells, reduced colony-forming ability in soft agar, and loss of tumorigenicity in athymic nude mice. To address the molecular consequences of constitutive IFNalpha synthesis, they examined the expression of four genes whose transcription has been shown to be responsive to IFN-mediated signal transduction and could be important to the observed antiproliferative and antitumor effects. Northern blot analysis revealed that changes in the levels of messenger (m)RNA for two of these genes, c-myc and mhc class I, are minor. However, mRNAs for oligoadenylate synthetase (OAS) as well as double-stranded RNA-activated protein kinase (PKR), which are not expressed in parental U118 cells, were constitutively expressed in IFNalpha transfectants. These results indicate a differential responsiveness among these four genes to constitutive IFNalpha expression, and suggest that the suppression of U118-transformed phenotypes by IFNalpha transfection may be mediated by the induction of specific IFN response genes thought to have a negative growth-regulatory function.
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PMID:Transfection of IFNalpha in human glioblastoma cells and tumorigenicity in association with induction of PKR and OAS gene expression. 892 99

We have isolated human and rat clones of the LIM motif-containing protein kinase, termed LIMK-2. LIMK-2 is related to the neuronally expressed LIM-kinase, whose hemizygous deletion appears to result in cognitive impairment in patients with Williams syndrome. The hallmark of this protein family is the presence of 1 or 2-terminal LIM motifs and an atypical C-terminal protein kinase domain. LIMK-2 mRNA was detected by Northern blot analysis in human tissues, most abundantly in placenta, lung, liver, and pancreas, and also in a variety of cell lines including neuronal, glioblastoma, and mammary carcinoma lines. The LIMK-2 transcript was also induced upon neuroectodermal differentiation of mouse P19 embryonal carcinoma cells. A 65 kDa recombinant LIMK-2 protein was identified in 293 cells stably transfected with a LIMK-2 expression vector. An in vitro kinase assay demonstrates LIMK-2 is autophosphorylated and exhibits serine/threonine kinase activity towards the exogenous substrate MBP. The endogenous 65 kDa LIMK-2 protein was detected in a variety of cell lines, and coprecipitates with a 140 kDa tyrosine phosphorylated protein, but was not itself tyrosine phosphorylated. At the subcellular level, LIMK-2 is localized in both the nucleus and in a Triton X-100 soluble fraction.
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PMID:Cloning and biochemical characterization of LIMK-2, a protein kinase containing two LIM domains. 908 16

In human glioblastoma A172 cells, interleukin-6 (IL-6) production was induced by interleukin-1 beta (IL-1 beta) and dibutyryl cyclic AMP. These cells have been shown to induce IL-6 production via a cAMP-protein kinase A system. Since calcitonin (CT) and calcitonin gene-related peptide (CGRP) are known to increase cAMP accumulation in murine and rat astrocytes, we examined whether these neuropeptides induced IL-6 production in A172 cells. Human CT and human CGRP increased IL-6 production and cAMP accumulation in a dose-dependent manner. A specific protein kinase A inhibitor, H-89, inhibited both CT- and CGRP-induced IL-6 production. CT and CGRP have been shown to cross-react with each other. To exclude the possibility of this cross-reactivity, we studied the additive effects of CT and CGRP and the inhibitory effects of specific inhibitors. When 100 nM CT was added, cAMP accumulation stimulated by 10 nM CGRP (the maximal dose) was increased. CGRP (8-37), a specific CGRP receptor inhibitor, inhibited cAMP accumulation and IL-6 production induced by CGRP, but did not inhibit these effects when they were induced by CT. Salmon CT (8-32), a specific inhibitor of the CT receptor, inhibited cAMP accumulation induced by CT, but did not inhibit the effect induced by CGRP. These results demonstrated that CT can induce IL-6 production via cAMP accumulation and the effects of CT are mediated via its own receptors.
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PMID:Protein kinase A-dependent IL-6 production induced by calcitonin in human glioblastoma A172 cells. 918 43

The p16INK4a gene product acts as a negative regulator of the cell cycle by binding to cyclin-dependent kinases (CDKs) 4 and 6, thereby inhibiting the formation of an active CDK/cyclin D complex. Deletion of the p16 locus has been observed in tumor cell lines and, less frequently, in primary human neoplasms. We analyzed 31 glioblastomas and identified 6 cases with hemizygous and 6 with homozygous deletions of the p16 locus. Eight of these cases showed a concurrent amplification of the EGFR gene (epidermal growth factor receptor) while the overall frequency was 35%. This close correlation suggests that deletion of the p16 chromosomal region constitutes another genetic hallmark of the primary glioblastoma, which rapidly develops de novo, without a less malignant precursor lesion and for which EGFR amplification is a characteristic genetic change. The p16 protein was not detectable in 15 of 22 glioblastomas but only 4 of these showed homozygous deletion of the gene. The alternative transcript p16 beta, for which a growth-suppressing function has been suggested, was co-expressed with p16 alpha mRNA in most cases. Hypermethylation of CpG islands in the 5' region of the p16 gene was identified in only 1 case, suggesting that this alternative mechanism of gene silencing is rarely responsible for loss of p16 expression in glioblastomas. Likewise, only 1 glioblastoma carried a p16 mutation and in addition, unexpectedly, a homozygous deletion of p16 in approximately 80% of tumor cells. This mutation, Arg24Pro, has previously been identified in a melanoma kindred.
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PMID:Hemizygous or homozygous deletion of the chromosomal region containing the p16INK4a gene is associated with amplification of the EGF receptor gene in glioblastomas. 933 10

We examined the effects of several kinds of protein kinase inhibitors against calcium/phospholipid-dependent protein kinase (PKC) and cAMP-dependent protein kinase (PKA) on heat-induced hsp72 gene expression in a human glioblastoma cell line (T98G) as a source of insight into the type of protein kinase contributing to its gene expression. When the cells were treated with 1-(5-isoquinolinesulphonyl)-2-methylpiperazine [(H7) a potent inhibitor of PKC, PKA, and others], the suppression of heat-induced Hsp72 accumulation was observed. Heat-induced Hsp72 accumulation was also suppressed by staurosporine (a potent inhibitor of PKC and PKA) or calphostin C [(CAL) a potent inhibitor of PKC] at high concentration (10 x IC50) but not at low concentration (1 x IC50). N-(2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide [(H89) a potent inhibitor of PKA] did not affect heat-induced Hsp72 accumulation at either low (1 x IC50) or high concentrations (10 x IC50). Combination treatment with CAL and H89 suppressed the heat-induced Hsp72 accumulation more strongly than did treatment with either inhibitor alone. Furthermore, the heat-induced DNA-binding activation of heat-shock factor (HSF) was suppressed by CAL at high concentration (10 x IC50), and combination treatment with CAL and H89 showed stronger suppression. In the H7 treatment, the clear suppression of HSF activation was observed even at low concentration (1 x IC50). In addition, the cellular content of Hsp72 increased after the treatment of PKC or PKA activator. These results suggest that not only PKC, but also PKA may play an important role in heat-induced hsp72 gene expression.
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PMID:Effects of protein kinase inhibitors on heat-induced hsp72 gene expression in a human glioblastoma cell line. 961 83

Glioblastomas are highly malignant tumors of the central nervous system that are resistant to radiation and chemotherapy [1]. We explored the role of the phosphatidylinositol (PI) 3-kinase signal transduction pathway in glioblastomas, as this pathway has been shown to inhibit apoptosis induced by cytokine withdrawal and the detachment of cells from the extracellular matrix [2]. Components of this pathway have been implicated in tumor development [3-6]. We show that glioblastoma cells, in contrast to primary human astrocytes, contain high endogenous protein kinase B (PKB/Akt) activity and high levels of PI 3,4,5-triphosphate (PI(3,4,5)P3) and PI(3,4)P2, the lipid products of PI 3-kinase. These glioblastoma cells express mutant forms of the putative 3' phospholipid phosphatase PTEN, also known as MMAC. Expression of wild-type PTEN derived from primary astrocytes, but not of mutant forms of PTEN, reduced the levels of 3' phosphoinositides and inhibited PKB/Akt activity. PTEN antagonized the activation of PKB/Akt by growth factors, by activated PI 3-kinase and by PI-dependent protein kinase-1 (PDK1), but did not antagonize the phospholipid-independent activation of PKB/Akt lacking the pleckstrin homology (PH) domain. These results suggest a role for PTEN in regulating the activity of the PI 3-kinase pathway in malignant human cells.
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PMID:Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. 979 39

Drosophila transcription factor cubitus interruptus (Ci) and its co-activator CRE (cAMP response element)-binding protein (CBP) activate a group of target genes on the anterior-posterior border in response to hedgehog protein (Hh) signaling. In the anterior region, in contrast, the carboxyl-truncated form of Ci generated by protein processing represses Hh expression. In vertebrates, three Ci-related transcription factors (glioblastoma gene products (GLIs) 1, 2, and 3) were identified, but their functional difference in Hh signal transduction is unknown. Here, we report distinct roles for GLI1 and GLI3 in Sonic hedgehog (Shh) signaling. GLI3 containing both repression and activation domains acts both as an activator and a repressor, as does Ci, whereas GLI1 contains only the activation domain. Consistent with this, GLI3, but not GLI1, is processed to generate the repressor form. Transcriptional co-activator CBP binds to GLI3, but not to GLI1. The trans-activating capacity of GLI3 is positively and negatively regulated by Shh and cAMP-dependent protein kinase, respectively, through a specific region of GLI3, which contains the CBP-binding domain and the phosphorylation sites of cAMP-dependent protein kinase. GLI3 directly binds to the Gli1 promoter and induces Gli1 transcription in response to Shh. Thus, GLI3 may act as a mediator of Shh signaling in the activation of the target gene Gli1.
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PMID:Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. 1007 17

Aberrant expression of the potent angiogenic cytokine, vascular endothelial growth factor (VEGF), has been demonstrated to be associated with most human solid tumors. Both transcriptional and post-transcriptional mechanisms have been shown to modulate VEGF expression in a multitude of cell types. Here we report that when protein kinase C (PKC) pathways were activated in human glioblastoma U373 cells by phorbol 12-myristate 13-acetate (PMA), VEGF mRNA expression was up-regulated via a post-transcriptional mRNA stabilization mechanism. PMA treatment exhibited no increase in VEGF-specific transcriptional activation as determined by run-off transcription assays and VEGF promoter-luciferase reporter assays. However, PMA increased VEGF mRNA half-life from 0.8 to 3.6 h which was blocked by PKC inhibitors but not by protein kinase A or cyclic nucleotide-dependent protein kinase inhibitors. When U373 cells were transfected with antisense oligonucleotide sequences to the translation start sites of PKC-alpha, -beta, -gamma, -delta, -epsilon, or -zeta isoforms, both PKC-alpha and -zeta antisense oligonucleotides showed substantial inhibition of PMA-induced VEGF mRNA. In addition, overexpression of PKC-zeta resulted in a strong constitutive up-regulation of VEGF mRNA expression. This study demonstrates for the first time that specific PKC isoforms regulate VEGF mRNA expression through post-transcriptional mechanisms.
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PMID:Role of protein kinase C isoforms in phorbol ester-induced vascular endothelial growth factor expression in human glioblastoma cells. 1033 29


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