Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hydrophobicity of biomaterials has been recognized as a limitation to the adequate function of anchorage-dependent cells when hydrophobic biomaterials are used for tissue engineering. This is due to flawed solid-state signals from cell adhesion. In this study, a recombinant osteopontin (rOPN17-169) fragment containing the cell adhesion motifs was expressed in E. coli and was precoated on the hydrophobic surface prior to osteoblastic MG63 cell culture. Precoating the hydrophobic surface with rOPN17-169 improved osteoblastic cell adhesion, which was blocked by soluble RGDS. The adhesion of MG63 cells to rOPN17-169 pre-coated surface-activated mitogen-activated protein kinases (MAPK) such as extracellular signal-receptor kinase 1/2, p38, and c-Jun N-terminal kinase (JNK). In addition, p38 MAPK was activated in response to a soluble factor of transforming growth factor-beta in the cells adhered to the hydrophobic surface via rOPN17-169. This suggests that rOPN17-169 precoated on the hydrophobic surface can allow osteoblastic cells to generate adhesion signals sufficient for cell adhesion, MAPK activation, and the cytokine activation of osteoblastic cells.
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PMID:MG63 osteoblastic cell adhesion to the hydrophobic surface precoated with recombinant osteopontin fragments. 1250 28

TATA binding protein (TBP) is a central transcription factor used by all three cellular RNA polymerases. Changes in the levels of TBP have been shown to have selective effects on gene activity. Overexpression of TBP has been recently shown to contribute to cellular transformation, and elevated levels of TBP occur in a clinically significant proportion of human colon tumors relative to matched normal tissue. To understand the mechanisms by which TBP is regulated, we have analyzed whether activation of the epidermal growth factor receptor (EGFR), a membrane-bound tyrosine receptor kinase that is activated in a large number of human cancers, can serve to regulate cellular TBP. We show that treatment of mouse epidermal cells with EGF produces an increase in TBP levels, which can be blocked with an EGFR-specific inhibitor. In contrast, TBP levels remain unchanged after EGF treatment of EGFR null cells. EGF-mediated increases in TBP are regulated at the transcriptional level, as transient expression of the human TBP promoter is induced with EGF. This regulatory event is dependent upon the downstream activation of Ras and requires the activation of p38, JNK, and ERK mitogen-activated protein kinases. The consequence of elevated TBP on gene expression was further determined. Transcription by RNA polymerase (Pol) I and III was induced by EGF. Directly overexpressing TBP also stimulated transcription from these promoters. Thus, we have identified a new and important target of EGFR signaling, TBP, that contributes to EGF-mediated stimulation of RNA Pol I- and III-dependent gene activity. Since the cellular levels of the products of these genes, tRNAs and rRNAs, determine the translational capacity of cells, this event may be an important contributor to the transforming function of EGF.
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PMID:Epidermal growth factor enhances cellular TATA binding protein levels and induces RNA polymerase I- and III-dependent gene activity. 1516 79

Many cytokines increase their receptor affinity for Janus kinases (JAKs). Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. Intriguingly, insulin acting through its own receptor kinase also activates JAK2. However, the impact of such activation on insulin action remains unknown. To determine the contribution of JAK2 to insulin signaling, we transfected L6 myotubes with siRNA against JAK2 (siJAK2), reducing JAK2 protein expression by 75%. Insulin-dependent phosphorylation of IRS1/2 and Shc was not affected by siJAK2, but insulin-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-related kinase, p38, and Jun NH2-terminal kinase and their respective upstream kinases MKK1/2, MKK3/6, and MKK4/7 was significantly lowered when JAK2 was depleted, correlating with a significant drop in insulin-mediated cell proliferation. These effects were reproduced by the JAK2 inhibitor AG490. Conversely, insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation were not affected by siJAK2. Interestingly, in two insulin-resistant states, siJAK2 led to partial restoration of Akt phosphorylation and glucose uptake stimulation but not of the MAPK pathway. These results suggest that JAK2 may depress the Akt to glucose uptake signaling axis selectively in insulin-resistant states. Inhibition of JAK2 may be a useful strategy to relieve insulin resistance of metabolic outcomes.
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PMID:Opposite effect of JAK2 on insulin-dependent activation of mitogen-activated protein kinases and Akt in muscle cells: possible target to ameliorate insulin resistance. 1656 15

The existing literature indicates a crucial role of p38 MAP (mitogen-activated protein) kinase (p38MAPK) and its downstream target MAPKAP kinase 2 (MK2) in ischemic preconditioning (IPC). Accordingly, deletion of MK2 gene should abolish the cardioprotective ability of IPC. Interestingly, we were able to partially precondition the hearts from MK2(-/-) knockout mice suggesting the existence of an as yet unknown alternative downstream target of p38MAPK. A recent study from our laboratory also determined a crucial role of CREB (cyclic AMP response element binding protein) in IPC. Since CREB is a downstream target of MSK-1 (mitogen- and stress-activated protein kinase-1) situated at the crossroad of ERK (extracellular receptor kinase) and p38MAPK signaling pathways, we reasoned that MSK-1 could be a downstream molecular target for p38MAPK and ERK signaling in the IPC hearts. To test this hypothesis, the rat hearts were subjected to IPC by four cyclic episodes of 5 min ischemia and 10 min reperfusion. As expected, IPC induced the activation of ERK1/2, p38MAPK, MK2 and HSP (heat shock protein) 27 as evidenced by their increased phosphorylation; and the inhibition of p38MAPK with SB203580 almost completely, and the inhibition of ERK1/2 with PD098059 partially, abolished cardioprotective effects of IPC. Inhibition of MSK-1 with short hairpin RNA (shRNA) also abolished the IPC-induced cardioprotection. SB203580 partially blocked the effects of MSK-1 suggesting that MSK-1 sits downstream of p38MAPK. shRNA-MSK-1 blocked the contribution of both p38MAPK and ERK1/2 as it is uniquely situated at the downstream crossroad of both of these MAP kinases. Although MSK-1 sits downstream of both ERK1/2 and p38MAPK, ERK1/2 activation appears to play less significant role compared to p38MAPK, since its inhibition blocked MSK activation only partially. Consistent with these results, shRNA-MSK-1 blocked the partial PC in MK2(-/-) hearts, and in combination with SB203580, completely abolished the PC effects in the wild-type hearts. The IPC-induced survival signaling was almost completely inhibited with SB203580, and only partially with PD 098059 as evidenced from the inhibition patterns of IPC induced activation of CREB, Akt and Bcl-2. Again SB203580 alone or in combination with shRNA-MSK-1 inhibited IPC induced survival signal comparatively, suggesting that MSK-1 exists downstream of p38MAPK. Taken together, these results indicate for the first time MSK-1 as an alternative (other than MK2) downstream target for p38MAPK, which also transmits survival signal through the activation of CREB.
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PMID:Ischemic preconditioning involves dual cardio-protective axes with p38MAPK as upstream target. 2323 Jun 4

Rap1 transduces nerve growth factor (NGF)/tyrosine receptor kinase A (TrkA) signaling in early endosomes, leading to sustained activation of the p44/p42 mitogen-activated protein kinases (MAPK1/2). However, the mechanisms by which NGF, TrkA and Rap1 are trafficked to early endosomes are poorly defined. We investigated trafficking and signaling of NGF, TrkA and Rap1 in PC12 cells and in cultured rat dorsal root ganglion (DRG) neurons. Herein, we show a role for both microtubule- and dynein-based transport in NGF signaling through MAPK1/2. NGF treatment resulted in trafficking of NGF, TrkA and Rap1 to early endosomes in the perinuclear region of PC12 cells where sustained activation of MAPK1/2 was observed. Disruption of microtubules with nocodazole in PC12 cells had no effect on the activation of TrkA and Ras. However, it disrupted intracellular trafficking of TrkA and Rap1. Moreover, NGF-induced activation of Rap1 and sustained activation of MAPK1/2 were markedly suppressed. Inhibition of dynein activity through overexpression of dynamitin (p50) blocked trafficking of Rap1 and the sustained phase of MAPK1/2 activation in PC12 cells. Remarkably, even in the continued presence of NGF, mature DRG neurons that overexpressed p50 became atrophic and most (>80%) developing DRG neurons died. Dynein- and microtubule-based transport is thus necessary for TrkA signaling to Rap1 and MAPK1/2.
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PMID:A functional dynein-microtubule network is required for NGF signaling through the Rap1/MAPK pathway. 1782 5

The rat secretory ductal obstruction model has been widely used to assess salivary gland injury, growth, and differentiation. In this study, a novel ductal obstruction and release procedure was used to explore the signaling pathways leading to salivary gland regeneration. Rats underwent bilateral parotid ductal obstruction in which the duct was occluded against a plastic disk subcutaneously and released by external ligature removal. This ductal obstruction/release procedure was validated to produce glandular atrophy and regeneration with histological analysis and periodic acid-Schiff staining. Immunoblot analysis indicated that during ductal obstruction and the early post-release period (day 7), expression of immunoreactive proliferating cell nuclear antigen and vimentin was increased in the parotid glands compared with sham-operated animals. Immunohistochemical staining and immunoblots revealed up-regulation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated receptor kinase (ERK)1/2, and p38 during the atrophic and regeneration phases of ductal obstruction/release. Similarly, increases in activated, i.e., phosphorylated, ERK1/2 (pERK1/2) and p38 (phospho-p38) were demonstrable in both ductal and recovering acinar cells, with pERKs expressed predominantly in the nuclei and phospho-p38 distributed throughout the cells. Furthermore, levels of epidermal growth factor (EGF) receptor and beta2-adrenergic receptor (beta2-AR) were elevated in the ligated glands and at day 7 post-release; beta1-AR levels did not change over the same time period. These results support the view that cell proliferation is involved in duct ligation-induced atrophy of the rat parotid gland and gland recovery upon ligature removal. Up-regulation of ERKs and p38, and the activation of these MAPKs by up-regulated EGF and beta2-ARs, may be important signaling components underlying glandular atrophy and subsequent regeneration.
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PMID:Mitogen-activated protein kinase up-regulation and activation during rat parotid gland atrophy and regeneration: role of epidermal growth factor and beta2-adrenergic receptors. 1817 19

We previously reported that basic fibroblast growth factor (FGF-2) stimulates the release of vascular endothelial growth factor (VEGF) via p44/p42 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of platelet-derived growth factor-BB (PDGF-BB) on FGF-2-induced VEGF release in MC3T3-E1 cells. PDGF-BB significantly enhanced the FGF-2-stimulated VEGF release. The amplifying effect of PDGF-BB was dose dependent in the range between 0.1 and 30 ng/ml. AG1295, a selective inhibitor of PDGF receptor kinase, which reduced the autophosphorylation of PDGF receptor-(R), suppressed the enhancement by PDGF-BB without affecting the FGF-2 effect. PDGF-BB failed to strengthen the FGF-2-induced phosphorylation of p44/p42 MAP kinase or SAPK/JNK. The amplification by PDGF-BB of FGF-2-stimulated VEGF release was reduced by PD98059, a specific inhibitor of MEK, or SP600125, a specific inhibitor of SAPK/JNK. These results strongly suggest that PDGF-BB potentiates FGF-2-stimulated VEGF release at a point downstream from p44/p42 MAP kinase and SAPK/JNK in osteoblasts.
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PMID:Potentiation by platelet-derived growth factor-BB of FGF-2-stimulated VEGF release in osteoblasts. 1860 Mar 99

In Arabidopsis, the CLAVATA (CLV) pathway operates in the regulation of the size of the stem cell population in the shoot apical meristem (SAM). CLV3 functions as a small peptide ligand to negatively regulate the expression of the WUSCHEL (WUS) transcription factor through three major receptor kinase complexes of CLV1, CLV2-SUPPRESSOR OF LLP1-2 (SOL2)/CORYNE (CRN) and recently identified RECEPTOR-LIKE PROTEIN KINASE 2 (RPK2)/TOADSTOOL 2 (TOAD2). Aiming to understand the precise molecular details of CLV3 signaling, we investigated the contribution of phospho-signaling, potentially regulated by these kinase complexes, to the CLV pathway. We detected CLV3-triggered CLV1 phosphorylation, which is also conditioned by the rest of the CLV receptors, presumably by their direct association. Our comprehensive analysis of the activities of the respective CLV receptors on mitogen-activated protein kinases (MAPKs) suggested that the precise balanced regulation of MAPK activity by the CLV receptors is likely to be key for SAM homeostasis.
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PMID:Mitogen-activated protein kinase regulated by the CLAVATA receptors contributes to shoot apical meristem homeostasis. 2096 98

Cocaine-mediated neuroadaptations in the prefrontal cortical-nucleus accumbens pathway underlie drug-seeking in animals with a cocaine self-administration (SA) history. Neuroplasticity in the cortico-accumbens pathway is regulated, in part, by the expression and availability of neurotrophic factors, such as BDNF. We have previously demonstrated that infusion of BDNF into the dorsomedial prefrontal cortex (dmPFC) immediately after the last of 10 cocaine SA sessions attenuates contextual, cue- and cocaine prime-induced reinstatement of cocaine-seeking (Berglind et al., 2007) and normalizes cocaine-induced disruption of glutamatergic transmission in the nucleus accumbens (Berglind et al., 2009). In the present study, the suppressive effect of intra-dmPFC BDNF on cocaine-seeking is shown to depend on Trk receptor-mediated activation of extracellular signal-regulated kinase (ERK) signaling in the dmPFC. The tyrosine kinase inhibitor, K252a, and the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), prevented BDNF's suppressive effects on cocaine-seeking. Vehicle-infused rats with a cocaine SA history showed significant decreases in ERK and cyclic AMP response element binding protein (CREB), but not Akt, phosphorylation after the final cocaine SA session that were reversed by intra-dmPFC BDNF. Additionally, BDNF's ability to normalize cocaine-mediated decreases in ERK and CREB phosphorylation was blocked by U0126, demonstrating that ERK/MAPK activation mediated the behavioral effects. This study elucidates a mechanism whereby BDNF/TrkB (tropomyosin receptor kinase B) activates ERK-regulated CREB phosphorylation in the dmPFC to counteract the neuroadaptations induced by cocaine SA and subsequent relapse to cocaine-seeking.
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PMID:The suppressive effect of an intra-prefrontal cortical infusion of BDNF on cocaine-seeking is Trk receptor and extracellular signal-regulated protein kinase mitogen-activated protein kinase dependent. 2124 6

Two novel, modified thymidine nucleosides, 5-phenylselenyl-methyl-2'-deoxyuridine (PhSe-T) and 5-methylselenyl-methyl-2'-deoxyuridine (MeSe-T), trigger reactive oxygen species (ROS) generation and DNA damage and thereby induce caspase-mediated apoptosis in human HL-60 cells; however, the mechanism leading to caspase activation and apoptotic cell death remains unclear. Therefore, we investigated the signaling molecules involved in nucleoside derivative-induced caspase activation and apoptosis in HL-60 cells. PhSe-T/MeSe-T treatment activated two mitogen-activated protein kinases (MAPKs), extracellular-receptor kinase (ERK) and p38, and induced the phosphorylation of two downstream targets of p38, ATF-2 and MAPKAPK2. In addition, the selective p38 inhibitor SB203580 suppressed PhSe-T/MeSe-T-induced apoptosis and activation of caspase-3, -9, -8, and -2, whereas the jun amino-terminal kinase (JNK) inhibitor SP600125 and the ERK inhibitor PD98059 had no effect. SB203580 and an ROS scavenger, tiron, inhibited PhSe-T/MeSe-T-induced histone H2AX phosphorylation, which is a DNA damage marker. Moreover, tiron inhibited PhSe-T/MeSe-T-induced phosphorylation of p38 and enhanced p38 MAP kinase activity, indicating a role for ROS in PhSe-T/MeSe-T-induced p38 activation. Taken together, our results suggest that PhSe-T/MeSe-T-induced apoptosis is mediated by the p38 pathway and that p38 serves as a link between ROS generation and DNA damage/caspase activation in HL-60 cells.
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PMID:p38 mitogen-activated protein kinase is a key regulator of 5-phenylselenyl- and 5-methylselenyl-methyl-2'-deoxyuridine-induced apoptosis in human HL-60 cells. 2214 47


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