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)

The multisite phosphorylation of the transcription factor ATF-2 was investigated using transformed embryonic fibroblasts from wild-type mice and mice deficient in c-Jun N-terminal kinases (JNK)1 and 2, and in the presence and absence of inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) and the classical MAP kinase cascade. In wild-type cells, p38 MAPK and extracellular signal-regulated protein kinase (ERK)1/2 were not rate limiting for the phosphorylation of Thr69, Thr71 or Ser90. In JNK-deficient cells, p38 MAPK substituted for JNK partially in the phosphorylation of Thr69 and p38 MAPK or ERK1/2 in the phosphorylation of Thr71. JNK was the only MAP kinase that phosphorylated Ser90 under the conditions examined.
...
PMID:Signalling pathways involved in multisite phosphorylation of the transcription factor ATF-2. 1530 44

Interferons (IFN)s are involved in numerous immune interactions during viral infections and contribute to both induction and regulation of innate and adaptive antiviral mechanisms. IFNs play a pivotal rule in the outcome of a viral infection, as demonstrated by the impaired resistance against different viruses in mice deficient for the receptors IFNAR-2 and IFNGR. During viral infections, IFNs are involved in numerous immune interactions as inducers, regulators, and effectors of both innate and adaptive antiviral mechanisms. IFN-alpha/beta is produced rapidly when viral factors, such as envelope glycoproteins, CpG DNA, or dsRNA, interact with cellular pattern-recognition receptors (PRRs), such as mannose receptors, toll-like receptors (TLRs), and cytosolic receptors. These host-virus interactions signal downstream to activate transcription factors needed to achieve expression from IFN-alpha/beta genes. These include IFN regulatory factor-3 (IRF-3), IRF-5, IRF-7, c-Jun/ATF-2, and NF-kappaB. In contrast, IFN-gamma is induced by receptor-mediated stimulation or in response to early produced cytokines, including interleukin-2 (IL-12), IL-18, and IFN-alpha/beta, or by stimulation through T cell receptors (TCRs) or natural killer (NK) cell receptors. IFNs signal through transmembrane receptors, activating mainly Jak-Stat pathways but also other signal transduction pathways. Cytokine and TCR-induced IFN-gamma expression uses distinct signal transduction pathways involving such transcription factors as NFAT, Stats and NF-kappaB. This results in induction and activation of numerous intrinsic antiviral factors, such as RNA-activated protein kinase (PKR), the 2-5A system, Mx proteins, and several apoptotic pathways. In addition, IFNs modulate distinct aspects of both innate and adaptive immunity. Thus, IFN-alpha/beta and IFN-gamma affect activities of macrophages, NK cells, dendritic cells (DC), and T cells by enhancing antigen presentation, cell trafficking, and cell differentiation and expression profiles, ultimately resulting in enhanced antiviral effector functions. This review focuses on the latest findings regarding induction and regulation of IFNs, primarily during the early phase of an antiviral immune response. Both cellular and molecular aspects are discussed from the perspective of host-virus interactions.
...
PMID:Induction and regulation of IFNs during viral infections. 1532 Sep 58

The urokinase plasminogen activator(uPA) system plays important roles in tumor cell invasion and metastasis. In the present study, we evaluated the effects of ATF-PAI2CD, a hybrid protein of the amino-terminal fragment of urokinase and mutant plasminogen activator inhibitor-2, on 95D cells in vitro and in vivo. Furthermore, our results support a current hypothesis that fusion protein blocks tumor invasion and motility by inhibiting localized pericellular proteolysis. Treatment of 95D cells with ATF-PAI2CD resulted in a dose-dependent decrease in tumor-cell invasion through matrigel, and ATF-PAI2CD was much more effective than PAI-2CD. In addition, extracellular regular protein kinase (ERK1/2) expression was downregulated and the adhesion ability to fibronectin was increased in 95D cells treated with the fusion protein, which was confirmed by cell adhesion assay. A high-concentration of ATF-PAI2CD caused a significant reduction in tumor volume and weight in BALB/c (nu/nu) mice female inoculated with human 95D cells (5 x 10(6)); the antitumor effects were significant, which demonstrated a 67.9+/-4.2% reduction in tumor growth compared with control mice. The number of lymphatic metastasis was significantly reduced in mice treated with high- and middle- concentrations of ATF-PAI2CD, whereas a low-concentration of ATF-PAI2CD failed to exhibit any antimetastatic effects. In conclusion, the results suggested that the hybrid protein has therapeutic potential for lung carcinoma and other tumors to inhibit tumor invasion and metastasis.
...
PMID:A hybrid protein of the amino-terminal fragment of urokinase and mutant plasminogen activator inhibitor-2 efficiently inhibits tumor cell invasion and metastasis. 1549 Feb 35

Polyomavirus large T antigen (LT) has a direct role in viral replication and a profound effect on cell phenotype. It promotes cell cycle progression, immortalizes primary cells, blocks differentiation, and causes apoptosis. While much of large T function is related to its effects on tumor suppressors of the retinoblastoma susceptibility (Rb) gene family, we have previously shown that activation of the cyclin A promoter can occur through a non-Rb-dependent mechanism. Here we show that activation occurs via an ATF/CREB site. Investigation of the mechanism indicates that large T can synergize with CREB family members to activate transcription. Experiments with Gal4-CREB constructs show that synergy is independent of CREB phosphorylation by protein kinase A. Examination of synergy with Gal4-CREB deletion constructs indicates that large T acts on the constitutive activation domain of CREB. Large T can bind to CREB in vivo. Genetic analysis shows that the DNA-binding domain (residues 264 to 420) is sufficient to activate transcription when it is localized to the nucleus. Further analysis of the DNA-binding domain shows that while site-specific DNA binding is not required, non-site-specific DNA binding is important for the activation. Thus, CREB binding and DNA binding are both important for large T activation of CREB/ATF sites. In contrast to previous models where large T transactivation occurred indirectly, these results also suggest that large T can act directly at promoters to activate transcription.
...
PMID:Activation of CREB/ATF sites by polyomavirus large T antigen. 1576 19

Trichothecene mycotoxins and other translational inhibitors activate mitogen-activated protein kinase (MAPKs) by a mechanism called the "ribotoxic stress response," which drives both cytokine gene expression and apoptosis in macrophages. The purpose of this study was to identify upstream kinases involved in the ribotoxic stress response using the trichothecene deoxynivalenol (DON) and the RAW 264.7 macrophage as models. DON (100 to 1000 ng/ml) dose-dependently induced phosphorylation of c-Jun N-terminal protein kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 MAPKs. MAPK phosphorylation in response to DON exposure occurred as early as 5 min, was maximal from 15 to 30 min, and lasted up to 8 h. Preincubation with inhibitors of protein kinase C, protein kinase A, or phospholipase C had no effect on DON-induced MAPK phosphorylation. In contrast, the Src family tyrosine kinase inhibitors, PP1 (4-amino-5-[4-methylphenyl)]-7-[t-butyl]pyrazolo[3,4-d]-pyrimidine) and, PP2 (4-amino-5-[4-chlorophenyl]-7-[t-butyl]pyrazolo[3,4-d]-pyrimidine) concentration-dependently impaired phosphorylation of all three MAPK families. PP1 suppressed DON-induced phosphorylation of the MAPK substrates c-jun, ATF-2, and p90(Rsk). MAPK phosphorylation by two other translational inhibitors, anisomycin and emetine, were similarly Src-dependent. PP1 reduced DON-induced increases in nuclear levels and binding activities of several transcription factors (NF-kappaB, AP-1, and C/EBP), which corresponded to decreases in TNF-alpha production, caspase-3 activation, and apoptosis. Tyrosine phosphorylation of hematopoeitic cell kinase (Hck), a Src found in macrophages, was detectable within 1 to 5 min after DON addition, and this was suppressed by PP1. Knockdown of Hck expression with siRNAs confirmed involvement of this Src in DON-induced TNF-alpha production and caspase activation. Taken together, activation of Hck and possibly other Src family tyrosine kinases are likely to be critical signals that precede both MAPK activation and induction of resultant downstream sequelae by DON and other ribotoxic stressors.
...
PMID:Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. 1577 66

The endoplasmic reticulum (ER) plays an important role in ischemic neuronal cell death. In order to determine the effect of dantrolene, a ryanodine receptor antagonist, on ER stress response and ischemic brain injury, we investigated changes in ER stress-related molecules, that is phosphorylated form of double-stranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), phosphorylated form of eukaryotic initiation factor 2alpha (p-eIF2alpha), activating transcription factor-4 (ATF-4), and C/EBP-homologous protein (CHOP), as well as terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in the peri-ischemic area and ischemic core region of rat brain after transient middle cerebral artery occlusion (MCAO). In contrast to the cases treated with vehicle, the infarct volume and TUNEL-positive cells were significantly reduced at 24 h of reperfusion by treatment with dantrolene. The immunoreactivities for p-PERK, p-eIF2alpha, ATF-4, and CHOP were increased at the ischemic peripheral region after MCAO, which were partially inhibited by dantrolene treatment. The present results suggest that dantrolene significantly decreased infarct volume and provided neuroprotective effect on rats after transient MCAO by reducing ER stress-mediated apoptotic signal pathway activation in the ischemic area.
...
PMID:The protective effect of dantrolene on ischemic neuronal cell death is associated with reduced expression of endoplasmic reticulum stress markers. 1592 66

Earlier we reported that a novel mitotic protein kinase, PDZ-binding kinase (PBK), is expressed in primary hematopoietic neoplasms. Recent reports have suggested a role for PBK in mitotic progression. In the present study, we demonstrate that PBK is down regulated during doxorubicin induced growth arrest of HL60 promyelocytic leukemia cells at least partly due to cell cycle-specific transcriptional regulation. Furthermore, we show that transcriptional control is mostly due to binding of transcription factors E2F and CREB/ATF to two distinct binding sites within the PBK promoter. This was demonstrated by: (i) electrophoretic mobility shift assays showing transcription factor binding within the PBK promoter at the putative E2F (-146bp) and CREB/ATF (-312bp) binding sites; (ii) Western immunoblot analysis of knockdown extracts from siRNA inhibition of transcription factor expression showing that PBK protein expression is dependent upon the presence of these transcription factors; (iii) codistribution of CREB factor and PBK in cell lines of disparate tissue origin; and (iv) luciferase reporter assays showing that PBK promoter activity is dependent on factor binding at intact E2F and CREB/ATF sites. These findings may provide insight into the mechanisms that upregulate PBK expression in proliferative hematologic malignancies and down regulate its expression following growth arrest of leukemic cells.
...
PMID:Expression of PDZ-binding kinase (PBK) is regulated by cell cycle-specific transcription factors E2F and CREB/ATF. 1617 62

Patulin (PAT), a mycotoxin mainly produced by Penicillium and Aspergillus, is frequently detected in moldy fruits and fruit products. Exposure of human embryonic kidney (HEK293) cells to PAT led to a dose- and time-dependent increase in the phosphorylation of two major mitogen-activated protein kinases (MAPKs), p38 kinase and c-Jun N-terminal kinase (JNK). The phosphorylated forms of MAPK kinase 4 (MKK4), c-Jun, and ATF-2 were also seen in PAT-treated cultures. The cell death caused by PAT was significantly reduced by the p38 kinase inhibitor, SB203580, but not by the JNK inhibitor, SP600125. Neither p38 kinase nor JNK played a role in the PAT-induced DNA damage. In PAT-treated cells, inactivation of double-stranded RNA-activated protein kinase R (PKR) by the inhibitor, adenine, markedly suppressed JNK and ERK phosphorylation. Treatment of HEK293 cells with PAT-cysteine adduct, a chemical derivative of PAT, showed no effect on MAPK signaling pathways, cell viability, or DNA integrity. These results indicate that PAT causes rapid activation of p38 kinase and JNK in HEK293 cells, but only the p38 kinase signaling pathway contributes to the PAT-induced cell death. PKR also plays a role in PAT-mediated MAPK activation.
...
PMID:Mycotoxin patulin activates the p38 kinase and JNK signaling pathways in human embryonic kidney cells. 1630 51

Phosphorylation (P-) of cAMP-response element-binding protein (CREB) by protein kinase A or mitogen-activated protein kinases was implicated in mediating the increased tyrosine hydroxylase (TH) gene expression after prolonged exposure to nicotine in vivo and in cell culture. We examined the time course and signaling pathways for phosphorylation of CREB and possible involvement of ATF-2. Treatment of PC12 cells with 200 microm nicotine triggered rapid but transient elevation of P-CREB followed by a second sustained rise after 2-5 h of continuous nicotine. In contrast, ERK1/2 was only phosphorylated with short term nicotine exposure. MEK inhibitor U0126 abolished nicotine-induced rise in P-ERK1/2, but not P-CREB, nor did it inhibit nicotine-evoked elevation in TH promoter activity, indicating that ERK1/2 was not needed for induction of TH gene expression by nicotine. In contrast, protein kinase A inhibitor H-89 or Ca(2+)/calmodulin-activated protein kinase inhibitor KN-93 reduced the nicotine-triggered rise in P-CREB and TH promoter activity. There was a delayed elevation of P-ATF-2 after 1 h of nicotine treatment, accompanied by increased ATF-2 protein. Upstream kinase JNK, but not p38, was phosphorylated especially after 5 min to 2 h of nicotine exposure. To examine the requirement for CREB and ATF-2, cells were transfected with dominant negative forms of ATF-2 or CREB. Both reduced the basal TH promoter activity and the response to nicotine. Knockdown of ATF-2 or CREB with siRNA did not alter basal TH promoter activity or mRNA but greatly attenuated the response to nicotine. The results suggest that both ATF-2 and CREB mediate activation of TH gene transcription by nicotine.
...
PMID:Prolonged activation of cAMP-response element-binding protein and ATF-2 needed for nicotine-triggered elevation of tyrosine hydroxylase gene transcription in PC12 cells. 1645 70

The interferon-induced serine/threonine protein kinase (PKR) has an essential role in cell survival and cell death after viral infection and under stress conditions, but the host genes involved in these processes are not well defined. We used human cDNA microarrays to identify, in infected cells, genes differentially expressed after PKR expression and analyzed the requirement of catalytic activity of the enzyme. To express PKR, we used vaccinia virus (VV) recombinants producing wild type PKR (VV-PKR) and the catalytically inactive mutant K296R (VV-PKR-K296R). Most regulated genes were classified according to biological function, including apoptosis, stress, defense, and immune response. Transcriptional changes detected by microarray analysis were confirmed for selected genes by quantitative real time reverse transcription PCR. A total of 111 genes were regulated specifically by PKR catalytic activity. Of these, 97 were up-regulated, and 14 were down-regulated. The ATF-3 transcription factor, involved in stress-induced beta-cell apoptosis, was up-regulated. Activation of endogenous PKR with a VV mutant lacking the viral protein E3L (VVDeltaE3L), a PKR inhibitor, triggered an increase in ATF-3 expression that was not observed in PKR(-/-) cells. Using null cells for ATF-3 and for the p65 subunit of NF-kappaB, we showed that induction of apoptosis by PKR at late times of infection was dependent on ATF-3 expression and regulated by NF-kappaB activation. Here, we identified human genes selectively induced by expression of active PKR in infected cells and linked ATF-3 to a novel mechanism used by PKR to induce apoptosis.
...
PMID:Human gene profiling in response to the active protein kinase, interferon-induced serine/threonine protein kinase (PKR), in infected cells. Involvement of the transcription factor ATF-3 IN PKR-induced apoptosis. 1661 40


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

---