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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TSH activates its specific receptor in thyroid cells and induces cAMP, a robust stimulator of thyroid cell proliferation. Conversely, cAMP is a potent inhibitor of growth in mouse fibroblasts. To dissect the signals mediating cAMP-dependent growth, we have expressed in mouse fibroblasts the human thyrotropin receptor (TSHR) or a constitutively active mutant, under the control of the tetracyclin promoter. Both TSHR and cAMP levels were modulated by tetracyclin. In the presence of serum, activation of TSHR by TSH induced growth arrest. In the absence of serum, cells expressing TSHR stimulated with TSH, replicated their DNA, but underwent apoptosis. Co-expression of cAMP-dependent protein kinase (PKA) regulatory subunit type II (RIIbeta) inhibited apoptosis and stimulated the growth of cells only in the presence of TSH. Expression of RIIbeta-PKA, in the absence of TSHR, induced apoptosis, which was reversed by cAMP. Growth, stimulated by TSHR-RIIbeta-PKA in mouse fibroblasts, was also dependent on Rap1 activity, indicating cAMP-dependent growth in thyroid cells. As for the molecular mechanism underlying these effects, we found that in normal fibroblasts, TSH induced AKT and ERK1/2 only in cells expressing TSHR and RII. Similarly, activation of TSHR increased cAMP levels greatly, but was unable to stimulate CREB phosphorylation and transcription of cAMP-induced genes in the absence of RII. These data provide a simple explanation for the anti-proliferative and proliferative effects of cAMP in different cell types and indicate that RII-PKAII complements TSHR action by stably propagating robust cAMP signals in cell compartments.
...
PMID:The expression of the thyroid-stimulating hormone (TSH) receptor and the cAMP-dependent protein kinase RII beta regulatory subunit confers TSH-cAMP-dependent growth to mouse fibroblasts. 1290 33

Injuries to the brain result in the decline of glial glutamate transporter expression within hours and a recovery after several days. One consequence of this disturbed expression seems to consist in the temporary accumulation of toxic extracellular glutamate levels followed by secondary neuronal cell death. Whereas evidence exists that the decline in glutamate transporter expression results from a loss of neuronal PACAP influences on astroglia, the mechanism(s) inducing the reexpression of glial glutamate transporters is presently unknown. We now demonstrate that the injury-induced growth factors EGF, TGFalpha, FGF-2, and PDGF all promote the expression of the glutamate transporters GLT-1 and/or GLAST in cultured cortical astroglia. In contrast, similar stimulatory influences were absent with GDNF and BDNF, growth factors not affected by brain injuries. The effects of EGF, TGFalpha, FGF-2, and PDGF on glial glutamate transport were only partly redundant and involved distinctly different signaling pathways. Unlike EGF, TGFalpha, and FGF-2, PDGF promoted GLT-1, but not GLAST expression and further failed to increase the maximal velocity of sodium-dependent glutamate uptake. Moreover, FGF-2 only affected glial glutamate transport when the RAF-MEK-ERK signaling pathway was concomitantly inhibited with PD98059. Depending on the extracellular growth factor and glutamate transporter subtype, the observed stimulatory effects required the activation of PKA, PKC, and/or AKT. We suggest that after brain injury, reactive processes may limit secondary neuronal cell death by promoting glial glutamate transport. The detailed knowledge of these compensatory mechanisms will eventually allow us to therapeutically interfere with glutamate-associated neuronal cell death in the brain.
...
PMID:Regulation of glial glutamate transporter expression by growth factors. 1295 96

Protein kinase B (PKB, or Akt), a downstream effector of phosphatidylinositol 3-kinase (PI-3-K), can play a critical role in regulating neuronal survival. Among known targets of PKB, glycogen synthase kinase-3 (GSK-3) is inhibited by PKB-mediated phosphorylation. Recent studies implicate GSK-3 as a physiologically relevant principal regulatory target of the PI-3-K/PKB survival pathway. Here we show that SB-216763 and SB-415286, selective small molecule inhibitors of GSK-3, protected cultured rat cerebellar granule neurons and hippocampal neurons against excitotoxicity mediated by NMDA and non-NMDA receptor agonists. Treatment with SB-216763 and SB-415286 was optimal when initiated 6-7 days before excitotoxin exposure. As GSK-3 can modulate transcriptional events, these results may provide insight into the identification of new neuroprotective targets.
...
PMID:Glycogen synthase kinase-3 inhibitors protect central neurons against excitotoxicity. 1296 Jul 65

The granulin-epithelin precursor, progranulin, PC-cell-derived growth factor or acrogranin, is a high molecular weight secreted mitogen. It is abundantly expressed in rapidly cycling epithelial cells, in the immune system and in neurons, such as cerebellar Purkinje cells. Progranulin contributes to tumorigenesis in diverse cancers, including breast cancer, clear cell renal carcinoma, invasive ovarian carcinoma and glioblastoma. It regulates the rate of epithelial cell division in responsive epithelial cells, and confers an invasive phenotype on these cells. It is involved in the wound response. During embryogenesis, progranulin accelerates blastocyst formation, and is a growth factor for trophectodermal cells. In the neonate, progranulin, regulates the hormone-dependent virilization of the hypothalamus. It activates phosphorylation of Shc, and p44/42 MAPK (mitogen activated protein kinase) in the ERK (extracellular regulated kinase) signaling pathway; PI3K (phosophatidyl inositol-3-kinase), AKT/protein kinase B, and p70S6kinase in the phosophatidyl inositol-3-kinase pathway; and focal adhesion kinase in the adhesion/motility pathway. The signaling properties of progranulin are apparently similar to those of classic growth factors, but the functional properties of progranulin distinguish it from these molecules. Deleting the insulin-like growth factor I receptor from murine embryonic fibroblasts blocks proliferation in response to all classic growth factors, such as epidermal growth factor, or platelet-derived growth factor, whereas progranulin retains mitotic activity on these cells. The defined biological actions of progranulin probably represent a small fraction of its overall functions. Transcriptome analyses show that the progranulin gene is induced in numerous situations that vary from obesity to the transcriptional response of cells to antineoplastic drugs. Here, the biological roles of progranulin will be reviewed, with an emphasis on cancer and cell proliferation.
...
PMID:Progranulin (granulin-epithelin precursor, PC-cell derived growth factor, acrogranin) in proliferation and tumorigenesis. 1297 94

Cells of the vasculature, including macrophages, smooth muscle cells, and endothelial cells, exhibit apoptosis in culture upon treatment with oxidized low density lipoprotein, as do vascular cells of atherosclerotic plaque. Several lines of evidence support the hypothesis that the apoptotic component of oxidized low density lipoprotein is one or more oxysterols, which have been shown to induce apoptosis through the mitochondrial pathway. Activation of the mitochondrial pathway of apoptosis is regulated by members of the BCL family of proteins. In this study, we demonstrate that, in the murine macrophage-like cell line P388D1, oxysterols (25-hydroxycholesterol and 7-ketocholesterol) induced the degradation of the prosurvival protein kinase AKT (protein kinase B). This led, in turn, to the activation of the BCL-2 homology-3 domain-only proteins BIM and BAD and down-regulation of the anti-apoptotic multi-BCL homology domain protein BCL-xL. These responses would be expected to activate the pro-apoptotic multi-BCL homology domain proteins BAX and BAK, leading to the previously reported release of cytochrome c observed during oxysterol-induced apoptosis. Somewhat surprisingly, small interfering RNA knockdown of BAX resulted in a complete block of the induction of apoptosis by 25-hydroxycholesterol.
...
PMID:AKT/protein kinase B regulation of BCL family members during oxysterol-induced apoptosis. 1455 20

A novel thermodynamically-balanced inside-out (TBIO) method of primer design was developed and compared with a thermodynamically-balanced conventional (TBC) method of primer design for PCR-based gene synthesis of codon-optimized gene sequences for the human protein kinase B-2 (PKB2; 1494 bp), p70 ribosomal S6 subunit protein kinase-1 (S6K1; 1622 bp) and phosphoinositide-dependent protein kinase-1 (PDK1; 1712 bp). Each of the 60mer TBIO primers coded for identical nucleotide regions that the 60mer TBC primers covered, except that half of the TBIO primers were reverse complement sequences. In addition, the TBIO and TBC primers contained identical regions of temperature- optimized primer overlaps. The TBC method was optimized to generate sequential overlapping fragments (approximately 0.4-0.5 kb) for each of the gene sequences, and simultaneous and sequential combinations of overlapping fragments were tested for their ability to be assembled under an array of PCR conditions. However, no fully synthesized gene sequences could be obtained by this approach. In contrast, the TBIO method generated an initial central fragment (approximately 0.4-0.5 kb), which could be gel purified and used for further inside-out bidirectional elongation by additional increments of 0.4-0.5 kb. By using the newly developed TBIO method of PCR-based gene synthesis, error-free synthetic genes for the human protein kinases PKB2, S6K1 and PDK1 were obtained with little or no corrective mutagenesis.
...
PMID:Thermodynamically balanced inside-out (TBIO) PCR-based gene synthesis: a novel method of primer design for high-fidelity assembly of longer gene sequences. 1460 36

The phosphatidylinositol 3-kinase (PI3K)/AKT protein kinase pathway is involved in cell growth, proliferation, and apoptosis. The functional activation of PI3K/AKT provides survival signals and blockade of this pathway may facilitate cell death. Downstream targets of PI3K-AKT include the proapoptotic protein BAD, caspase-9, NF-kappaB, and Forkhead. We have previously reported that BAD is constitutively phosphorylated in primary acute myeloid leukemia (AML) cells, a post-transcriptional modification, which inactivates its proapoptotic function. In this study, we tested the hypothesis that the inhibition of PI3K by LY294002 results in the dephosphorylation of AKT and BAD, and thus promote leukemia cell apoptosis. We investigated the effects of LY294002 in megakaryocytic leukemia-derived MO7E cells, primary AML and normal bone marrow progenitor cells. In MO7E cells, LY294002 reduced AKT kinase activity, induced dephosphorylation of AKT and BAD, and increased apoptosis. Concomitant inhibition of mitogen-activated protein kinase signaling or combination with all-trans retinoic acid further enhanced apoptosis of leukemic cells. In primary AML samples, clonogenic cell growth was significantly reduced. Normal hematopoietic progenitors were less affected, suggesting preferential targeting of leukemia cells. In conclusion, the data suggest that the inhibition of the PI3K/AKT signaling pathway restores apoptosis in AML and may be explored as a novel target for molecular therapeutics in AML.
...
PMID:Inhibition of phosphatidylinositol 3-kinase dephosphorylates BAD and promotes apoptosis in myeloid leukemias. 1462 71

In B16 melanoma cells, cyclic adenosine monophosphate inhibits the phosphatidylinositol-3-kinase and the phosphatidylinositol-3-kinase inhibitor, LY294002, stimulates melanogenesis. However, the molecular mechanisms, by which phosphatidylinositol-3-kinase inhibition increases melanogenesis remained to be identified. In this study, we show that LY294002 up-regulates the expression of the melanogenic enzymes, tyrosinase and Tyrp1, through a transcriptional mechanism that involves microphthalmia associated transcription factor, a basic helix-loop-helix transcription factor, which plays a key role in melanocyte survival and differentiation. Further, we observe that LY294002 increases the intracellular content of microphthalmia associated transcription factor, thereby demonstrating that microphthalmia associated transcription factor is also a convergence point of the phosphatidylinositol-3-kinase signaling pathway. Finally, our results indicate that LY294002 controls microphthalmia associated transcription factor at the transcriptional level through distal regulatory element that remain to be identified. Interestingly, we have recently reported that cAMP-elevating agents, through a phosphatidylinositol-3-kinase/AKT inhibition and a glycogen synthase kinase 3beta activation, may stimulate microphthalmia associated transcription factor binding to its target sequence, suggesting that inhibition of the phosphatidylinositol-3-kinase is implicated in the stimulation of melanogenesis at different levels. Thus, the results presented in this report strengthen the importance of the phosphatidylinositol-3-kinase pathway in the regulation of melanogenesis and emphasize the complexity of the cyclic adenosine monophosphate signaling that controls melanocyte differentiation and melanogenesis.
...
PMID:Microphthalmia associated transcription factor is a target of the phosphatidylinositol-3-kinase pathway. 1463 2

Intermittent hypoxia (IH) during sleep induces temporally defined increases in apoptosis within vulnerable brain regions such as the hippocampal CA1 region in rats. Protein kinase B (AKT) has emerged as major signal transduction protein underlying inhibition of apoptosis and consequent increases in cell survival. Sprague Dawley adult male rats were exposed during sleep to IH or to normoxia (RA) for periods ranging from 0 to 30 days, and expression of total and phosphorylated AKT, of forkhead family members FKHR and FKHRL1, and of glycogen synthase kinase 3beta (GSK3beta) was assessed. Decreases in phosphorylation occurred as early as 1 h IH exposure, reached a nadir at 6 h-3 days, and then progressively returned to baseline levels at 14-30 days. Phosphorylated AKT and GSK3beta were intensely expressed and highly colocalized within neuronal cells (Neu-N positive) in the CA1 region. Thus, IH induces time-dependent biphasic changes in AKT survival pathways within the CA1 region that are temporally correlated with the initial increases and subsequent decreases in neuronal apoptosis.
...
PMID:Intermittent hypoxia induces time-dependent changes in the protein kinase B signaling pathway in the hippocampal CA1 region of the rat. 1467 60

Taxol (paclitaxel) and Taxotere (docetaxel) are considered as two of the most important anti-cancer chemotherapy drugs. The cytotoxic action of these drugs has been linked to their ability to inhibit microtubule depolymerization, causing growth arrest and subsequent cell death. Studies by a number of laboratories have also linked suppression of mitogen activated protein kinase (MAPK) signaling to enhanced Taxol toxicity. The present study examined the interactions of the semi-synthetic taxane Taxotere with MEK1/2 inhibitors in epithelial tumor cells. Concurrent treatment of MDA-MB-231 mammary and DU145 prostate carcinoma cells with Taxotere and MEK1/2 inhibitor resulted in protection from the anti-proliferative effects of Taxotere in MTT assays. In contrast, in MCF-7 mammary cells, concurrent Taxotere and MEK1/2 inhibitor treatment weakly enhanced the anti-proliferative effects of the taxane. Sequential treatment of MDA-MB-231 and MCF-7 cells with Taxotere followed by MEK1/2 inhibitor also enhanced the anti-proliferative effects of the taxane in MTT assays. However, no enhancement was observed in DU145 or PC-3 cells. Colony formation assays, including isobologram analyses, provided a more definitive demonstration that MCF-7 and MDA-MB-231 cells were sensitized to the toxic effects of Taxotere by U0126. Similar data were observed using Laulimalide, which binds to tubulin at a different site to Taxotere. The enhancement in Taxotere anti-proliferative effects by U0126 correlated with increased cell killing, 48-72h after treatment of cells that was blocked by inhibition of caspase 9, but not caspase 8, function. This observation was associated with prolonged suppression of ERK1/2 and AKT activity, without alteration in either p38 or JNK1/2 activity. Collectively these findings demonstrate that sequential administration of Taxotere followed by MEK1/2 inhibition can lead to increased cell death and loss of reproductive capacity in some, but not all, human tumor cells.
...
PMID:Sequence dependent exposure of mammary carcinoma cells to Taxotere and the MEK1/2 inhibitor U0126 causes enhanced cell killing in vitro. 1468 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---