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)

Epidemiological studies have revealed an inverse correlation between the intake of cruciferous vegetables and the risk of certain types of cancer. In animal studies, results suggest that the anti-cancerous effect of cruciferous vegetables is due to isothiocyanates that exist as thioglucoside conjugates in a variety of edible plants, including broccoli cabbage for example. Among isothiocyanates (ITC), Sulforaphane (SF) has received a great deal of interest due to its potent anti-tumoral properties in carcinogen-treated animals. The molecular pathways mediating the effects of SF have not been fully elucidated. However, many studies have shown that SF (as well as other ITCs) can induce phase II drug metabolizing enzymes in vitro as well as in animals. This commonly occurs via the activation of a basic leucine zipper transcription factor, Nrf2. In addition, accumulating evidence now indicates that SF can inhibit the proliferation of cancer cells in culture through the induction of cell cycle arrest via the regulation of cell cycle protein levels and/or cyclin-dependent kinase activity, tubulin polymerization and histone acetylation. Furthermore, ITCs have been shown to induce apoptotic cell death via a P53 dependent or independent pathway. Here, it is proposed to review the different intracellular targets involved in the in vitro effects of SF in various cancer cell lines. The relationship will then be discussed that exists between the various cell signaling pathways involved in this effect, and finally, the important aspects will be identified that must be addressed to fully understand the exact mechanism of action of SF.
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PMID:Signaling pathways and intracellular targets of sulforaphane mediating cell cycle arrest and apoptosis. 1652 43

Androgen receptor (AR) is a ligand-induced transcriptional factor, which plays an important role in the normal development of prostate as well as in the progression of prostate cancer. Numerous coactivators, which associate with AR and function to remodel chromatin and recruit RNA polymerase II to enhance the transcriptional potential of AR, have been identified. Among these coactivators, few are protein kinases. In this study, we describe the characterization of a novel protein kinase, male germ cell-associated kinase (MAK), which serves as a coactivator of AR. We present evidence, which indicates that (a) MAK physically associates with AR (MAK and AR are found to be coprecipitated from cell extracts, colocalized in nucleus, and corecruited to prostate-specific antigen promoter in LNCaP as well as in transfected cells); (b) MAK is able to enhance AR transactivation potential in an androgen- and kinase-dependent manner in several prostate cancer cells and synergize with ACTR/steroid receptor coactivator-3 coactivator; (c) small hairpin RNA (shRNA) knocks down MAK expression resulting in the reduction of AR transactivation ability; (d) MAK-shRNA or kinase-dead mutant, when introduced into LNCaP cells, reduces the growth of the cells; and (e) microarray analysis of LNCaP cells carrying kinase-dead MAK mutant showed a significant impediment of AR signaling, indicating that endogenous MAK plays a general role in AR function in prostate cancer cells and likely to be a general coactivator of AR in prostate tissues. The highly restricted expression of this kinase makes it a potentially useful target for intervention of androgen independence.
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PMID:Male germ cell-associated kinase, a male-specific kinase regulated by androgen, is a coactivator of androgen receptor in prostate cancer cells. 1695 Nov 54

As we previously reported, cAMP and p38 MAPK instead of protein kinase A were involved in beta-adrenergic receptor (beta-AR)-mediated interleukin-6 (IL-6) production in mouse cardiac fibroblasts. Besides kinases, phosphatases may also be involved in IL-6 gene regulation. To study the role of protein tyrosine phosphatases (PTPs) in beta-AR-mediated IL-6 production, we selected the most widely used PTP inhibitor, phenylarsine oxide (PAO). We found that PAO dose-dependently inhibited the IL-6 release in response to beta-AR agonist isoproterenol (ISO) in mouse cardiac fibroblasts. This effect was probably due to the inhibition of PTPs, resulting in increased tyrosine phosphorylation, since genistein, an inhibitor of protein tyrosine kinases further potentiated ISO-induced IL-6 production and could partially reverse the inhibitory effect of PAO. PAO also significantly inhibited the IL-6 production by forskolin, an adenylyl cyclase (AC) activator. Furthermore, PAO dose-dependently inhibited the increased cAMP accumulation by either ISO or forskolin and suppressed the phosphorylation of CREB, an important transcriptional factor for IL-6 gene expression. But PAO did not affect the activation of p38 MAPK by ISO. Although PAO was also reported to inhibit NADPH oxidase, the inhibition of NADPH oxidase by its specific inhibitor, diphenylene iodonium (DPI) could not suppress beta-AR-mediated IL-6 production, suggesting that NADPH oxidase may not contribute to the inhibitory effect of PAO on IL-6 production. To our knowledge, this is the first report that PAO can inhibit ISO-induced IL-6 expression and CREB phosphorylation, demonstrating that PTPs may negatively regulate beta-AR-mediated IL-6 production. This study may also further our understanding of beta-AR signaling and provide potential therapeutic targets for the treatment of heart diseases.
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PMID:Phenylarsine oxide inhibited beta-adrenergic receptor-mediated IL-6 secretion: inhibition of cAMP accumulation and CREB activation in cardiac fibroblasts. 1714 Nov 99

Id1, an inhibitory partner of basic-helix-loop-helix transcriptional factors, has recently been recognized as a potent contributor to angiogenesis. However, the molecular mechanism underlying its role in angiogenesis remains essentially unknown. Herein we demonstrate the subcellular localization of Id1 to be altered depending on the cellular context of vascular endothelial cells. Id1 was localized in the nuclei of human umbilical vein endothelial cells (HUVECs) cultured on uncoated plates, whereas it was translocated to the cytoplasm in HUVECs on Matrigel along with the formation of capillary-like structures. Treatment with the nuclear export inhibitor leptomycin B and mutagenesis analysis using green fluorescent protein-fused Id1 revealed CRM1/exportin-dependent nuclear export of Id1 in HUVECs on Matrigel. This nuclear export of Id1 was inhibited by protein kinase A (PKA) activation by dibutyryl cyclic AMP and forskolin but was promoted by PKA inactivation by H-89 and MDL-12,330A. Mutagenesis analysis of Id1 showed the phosphorylation of Ser-5 to possibly mediate the effect of PKA. These results suggest the function of Id1 as a transcriptional factor to be controlled by nucleocytoplasmic shuttling during angiogenesis and that PKA might be involved in this process. This may serve as a novel mechanism regulating angiogenesis and as a possible target for therapeutic vascular regeneration.
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PMID:Protein kinase A-regulated nucleocytoplasmic shuttling of Id1 during angiogenesis. 1741 91

Development in multicellular organisms is subject to both environmental and internal signals. In Dictyostelium, starvation induces amoebae to form migratory slugs that translocate from subterranean areas to exposed sites, where they culminate to form sessile fruiting bodies. Culmination, thought to be regulated by anterior tip cells, is selectively suppressed by mild hypoxia by a mechanism that can be partially overridden by another environmental signal, overhead light, or genetic activation of protein kinase A. Dictyostelium expresses, in all cells, an O2-dependent prolyl 4-hydroxylase (P4H1) required for O-glycosylation of Skp1, a subunit of E3SCF-Ub-ligases. P4H1-null cells differentiate the basic pre-stalk and pre-spore cell types but exhibit a selectively increased O2 requirement for culmination, from approximately 12% to near or above ambient (21%) levels. Overexpression of P4H1 reduces the O2 requirement to <5%. The requirement for P4H1 can be met by forced expression of the active enzyme in either pre-stalk (anterior) or pre-spore (posterior) cells, or replaced by protein kinase A activation or addition of small numbers of wild-type cells. P4H1-expressing cells accumulate at the anterior end, suggesting that P4H1 enables transcellular signaling by the tip. The evidence provides novel genetic support for the animal-derived O2-sensor model of prolyl 4-hydroxylase function, in an organism that lacks the canonical HIFalpha transcriptional factor subunit substrate target that is a feature of animal hypoxic signaling.
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PMID:Prolyl 4-hydroxylase-1 mediates O2 signaling during development of Dictyostelium. 1769 11

Signal transduction mechanisms mediating estradiol regulatory signals in the adrenal cortex were studied in rats. The effect of estradiol benzoate treatment on corticosteroids secretion, levels of ERK1/2, JNK, p38 mitogen-activated protein kinases, transcription factors c-Jun and c-Fos in adrenal cortex were investigated. The level of ERK1/2 was increased 1.7-fold in adrenocortical tissue after injections (3 days, 100 mkg per rat) of estradiol. However, the level of p38 kinase and protein kinase JNK was not changed in these conditions. The transcription factor AP-1, which includes c-Fos and c-Jun factors, is involved in realization of estradiol signal transduction. The level of c-Fos protein raised 1.8-fold after estradiol treatment, c-Jun protein was not increased. We conclude that ERK1/2 kinase and transcriptional factor c-Fos mediate fast estrogen signal transduction in adrenocorticocytes.
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PMID:[Effect of mitogen-activated protein kinases and transcriptional factor c-Fos on estradiol signal transduction in the rat adrenocorticocytes]. 1830 31

Manipulation of gene expression in melanocytes is an important tool for studying pigment cell biology. We constructed transgenic mice in which Cre recombinase was placed under the control of regulatory elements from the Microphthalmia-associated transcriptional factor (Mitf) gene using bacterial artificial chromosome (BAC). Bacterial artificial chromosome that contained either 50 or 108 kb DNA 5' to the melanocyte-specific (1M) transcriptional start site gave rise to transgenic lines in which Cre is expressed specifically in cells of the melanocyte lineage, as judged by activation of the Gt(Rosa)26(tm1Sor)(R26R) reporter locus. Activation of R26R is first detectable in melanoblasts of midgestation embryos, and completely marks all melanocyte components of the skin in postnatal animals. To test the utility of the MitfCre transgene, we used a loxP-targeted allele of the protein kinase A alpha catalytic subunit (Prkaca), modified such that Cre-mediated recombination activates PKA signaling. On an agouti background, animals carrying both the MitfCre transgene and the targeted Prkaca allele (CalphaR) exhibited a darker coat color than control littermates, due to a shift from pheomelanin to eumelanin synthesis. Our results confirm that PKA signaling is a key component of pigment type-switching, and provide a new tool for studying pigment cell biology.
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PMID:Melanocyte-lineage expression of Cre recombinase using Mitf regulatory elements. 1835 44

Retinopathy, a largely microvascular complication, affects over 80% of patients with diabetes for 20 years. The purpose of this study is to investigate the effect of diabetes on the activation of H-Ras, a small molecular weight G-protein that regulates cell fate, in the retinal microvessels. Microvessels were prepared from freshly isolated retina from streptozotocin diabetic rats or 30% galactose-fed rats by hypotonic lysis method. Ras activation was quantified by Raf-1 binding assay, and the activation of the signaling proteins, Raf-1 and mitogen activated protein (MAP) kinase, by quantifying their gene transcripts (RTPCR) and/or by protein expression (western blot). Two months of diabetes or experimental galactosemia activated H-Ras (Raf-binding assay) in the retinal microvessels by over 40% and 70% respectively compared to the values obtained from normal rat retinal microvessels. In the same diabetic rats the gene transcripts of H-Ras and its effector protein Raf-1 were elevated by 30% and 135% respectively with their protein expressions elevated by about 25% each, and this was paralleled by similar increases in the protein expressions of H-Ras and Raf-1 in experimentally galactosemic rats. Diabetes increased the gene expression of Ras-Raf-1 downstream signaling protein MAP kinase by over 50%, and that of nuclear transcriptional factor by 25-30%. This activation of H-Ras in retinal microvessels implies that its signaling pathway, in part, could be contributing to the microvascular pathology characteristic of diabetic retinopathy. Comparable activation of H-Ras and its signaling cascade in the retinal microvessels from experimentally galactosemic rats suggests that H-Ras activation is not due to insulin deficiency. Regulation of Ras function could provide important target in the complex approach to inhibit the pathogenesis of diabetic retinopathy.
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PMID:Diabetes regulates small molecular weight G-protein, H-Ras, in the microvasculature of the retina: implication in the development of retinopathy. 1851 35

Salt stress is an environmental factor that severely impairs plant growth and productivity. Salinity-induced transcript accumulation was monitored in the salt-sensitive Arabidopsis thaliana and the related salt-tolerant Lobularia maritima using cDNA-arrays with expressed sequence tags derived from a cDNA subtraction library of salt-stressed L. maritima. The expression profiles revealed differences of the steady state transcript regulation in A. thaliana and L. maritima in response to salt stress. The differentially expressed transcripts include those involved in the control of gene expression as a transcription factor II homologue as well as signal transduction elements such as a serine/threonine protein kinase, a SNF1-related protein kinase AKIN10 homologue, and protein phosphatase 2C. Other ESTs with differential regulation patterns included transcripts encoding proteins with function in general stress responses and defense and included a peroxidase, dehydrins, enzymes of lipid and nitrogen metabolism, and functionally unclassified proteins. In a more detailed analysis the basic leucine zipper transcription factor AtbZIP24 showed differential transcript abundance in A. thaliana and L. maritima in response to salt stress. Transgenic AtbZIP24-RNAi lines showed improved growth and development under salt stress that was correlated with changed Cl(-) accumulation. The data indicate that AtbZIP24 functions as a transcriptional repressor in salt-stressed A. thaliana that negatively regulates growth and development under salinity in context of controlling Cl(-) homeostasis. Monitoring the differential and tissue specific global regulation of gene expression during adaptation to salinity in salt-sensitive and halotolerant plants is a promising and powerful approach to identify novel elements of plant salt stress adaptation.
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PMID:Differential transcript regulation in Arabidopsis thaliana and the halotolerant Lobularia maritima indicates genes with potential function in plant salt adaptation. 1870 23

Circulating insulin-like growth factor-1 (IGF-1) levels are linked to cardiac performance and lifespan. However, the role of IGF-1 levels in aging-associated cardiac dysfunction has not been defined. This study was designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on aging-induced cardiomyocyte contractile and intracellular Ca(++) dysfunction. Cardiomyocytes were isolated from young (2- to 4-month-old) and old (24- to 26-month-old) male C57BL/6 and LID mice. Cardiomyocyte contractile and intracellular Ca(++) transient properties were evaluated, including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), electrically stimulated change in fura-fluorescence intensity (DeltaFFI), and intracellular Ca(++) decay rate. Aged C57BL/6 myocytes displayed reduced PS, +/-dL/dt and DeltaFFI as well as prolonged TR(90) and intracellular Ca(++) decay. IGF-1 deficiency decreased +/-dL/dt, and prolonged TR(90) with little change in other mechanical indices. Interestingly, LID dampened aging-induced changes in cardiomyocyte function. Aging and IGF-1 deficiency both contributed to whole-body glucose intolerance. Aging downregulated expression of Akt, Klotho, and pAMPK, whereas it upregulated p53 expression, the effects of which were cancelled by IGF-1 deficiency. Aging and IGF-1 deficiency significantly reduced expression of the transcriptional factor Foxo3a without an overt effect on the mammalian target of rapamycin (mTOR) level. Collectively, these data depicted that IGF-1 deficiency may reduce the cardiomyocyte sensitivity to aging-induced mechanical dysfunction. Our data suggest that regulation of Akt, p53, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and Klotho may play a role, at least in part, in IGF-1 deficiency-induced "desensitization" of cardiac aging.
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PMID:Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction. 1872 5


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