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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
...
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

Repair of injured renal epithelium is thought to be mediated by surviving renal proximal tubular cells (RPTC) that must dedifferentiate to allow the proliferation and migration necessary for epithelial regeneration. RPTC then redifferentiate to restore tubular structure and function. Current models suggest that epidermal growth factor receptor (EGFR) activation is required for dedifferentiation characterized by enhanced vimentin expression, decreased N-cadherin expression, spindle morphology, and loss of apical-basal polarity after injury. Because an in vitro model of RPTC redifferentiation has not been reported, and the mechanism(s) of redifferentiation has not been determined, we used rabbit RPTC in primary cultures to address these issues. H2O2 induced the dedifferentiated phenotype that persisted >48 h; redifferentiation occurred spontaneously in the absence of exogenous growth factors after 72 to 120 h. Phosphorylation of two tyrosine residues of EGFR increased 12 to 24 h, peaked at 24 h, and declined to basal levels by 48 h after injury. EGFR inhibition during dedifferentiation restored epithelial morphology and apical-basal polarity, and it decreased vimentin expression to control levels 24 h later. In contrast, exogenous epidermal growth factor addition increased vimentin expression and potentiated spindle morphology. p38 mitogen-activated protein kinase (MAPK) and transforming growth factor (TGF)-beta receptor inhibitors did not affect redifferentiation after H2O2 injury. Similar results were observed in a mechanical injury model. These experiments represent a new model for the investigation of RPTC redifferentiation after acute injury and identify a key regulator of redifferentiation: EGFR, independent of p38 MAPK and the TGF-beta receptor.
...
PMID:Regulation of dedifferentiation and redifferentiation in renal proximal tubular cells by the epidermal growth factor receptor. 1827 Mar 18

Basal cell carcinoma (BCC) of the skin is a highly compact, non-metastatic epithelial tumour type that may arise from the aberrant propagation of epidermal or progenitor stem cell (SC) populations. Increased expression of GLI1 is a common feature of BCC and is linked to the induction of epidermal SC markers in immortalized N/Tert-1 keratinocytes. Here, we demonstrate that GLI1 over-expression is linked to additional SC characteristics in N/Tert-1 cells including reduced epidermal growth factor receptor (EGFR) expression and compact colony formation that is associated with repressed extracellular signal-regulated kinase (ERK) activity. Colony formation and repressed ERK activity remain evident when EGFR is increased exogenously to the basal levels in GLI1 cells revealing that ERK is additionally inhibited downstream of the receptor. Exposure to epidermal growth factor (EGF) to increase ERK activity and promote migration negates GLI1 colony formation with cells displaying an elongated, fibroblast-like morphology. However, as determined by Snail messenger RNA and E-cadherin protein expression this is not associated with epithelial-mesenchymal transition (EMT), and GLI1 actually represses induction of the EMT marker vimentin in EGF-stimulated cells. Instead, live cell imaging revealed that the elongated morphology of EGF/GLI1 keratinocytes stems from their being 'stretched' due to migrating cells displaying inefficient cell-cell detachment and impaired tail retraction. Taken together, these data suggest that GLI1 opposes EGFR signalling to maintain the epithelial phenotype. Finally, ERK activity was predominantly negative in 13/14 BCCs (superficial/nodular), indicating that GLI1 does not routinely co-operate with ERK to induce the formation of this common skin tumour.
...
PMID:GLI1 repression of ERK activity correlates with colony formation and impaired migration in human epidermal keratinocytes. 1828 Dec 51

Cardiac differentiation involves cross-regulation of several transcription factors, such as Mef2C, regulated by p38alpha MAP kinase. We analysed the role of p38alpha in cardiac differentiation. Either the absence or inhibition of p38alpha impairs MEF2C nuclear localization in cardiomyocytes, colocalising with vimentin at the perinuclear region. As a consequence, expression of the Mef2C targets, ANF and myocardin, is drastically downregulated. In contrast, Mlc2v and crt are mainly unaltered, probably by the strong Mef2B upregulation, conpensating for the impaired Mef2C transactivity. In addition, p38alpha deficiency leads to a decrease in the phosphorylated Mlc2v fraction and alpha-actinin accumulation causing sarcomere disorganisation. We propose a critical role for p38alpha in early stages of cardiac differentiation by modulation of Mef2C localisation and sarcomeric assembly.
...
PMID:A role for p38alpha mitogen-activated protein kinase in embryonic cardiac differentiation. 1831 11

Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to late diagnoses and a lack of effective treatment options. Epidermal growth factor receptor (EGFR)-targeted therapies have been effective in other cancers. However, erlotinib and cetuximab have shown only modest efficacy in clinical trials of HCC. We examined epithelial-to-mesenchymal transition (EMT) as a determinant of sensitivity of HCC to EGFR inhibitors. A panel of 12 human hepatoma cell lines were classified as epithelial or mesenchymal based on their expression of E-cadherin and vimentin. The resulting classification correlated with a previous microarray analysis of human hepatoma cell lines whereby the mesenchymal cell lines were shown to have increased expression of genes involved in metastasis and invasion. Sensitivity to erlotinib, gefitinib, and cetuximab was assessed and the epithelial cell lines were found to be significantly more susceptible to all three agents. Analysis of the EGFR pathway showed that EMT status was independent of EGFR expression or downstream extracellular signal-regulated kinase activation and only the epithelial cell lines expressed ErbB3. Interestingly, mesenchymal cells resistant to EGFR inhibitors had increased AKT and signal transducer and activator of transcription-3 activation through elevated expression of integrin-linked kinase (ILK). Mesenchymal cell lines were therefore experimentally transformed with kinase-inactive ILK (KI-ILK) with a resulting decrease in ILK activity and activation of AKT. KI-ILK transformants showed increased sensitivity to EGFR inhibitors both in vitro and in an in vivo xenograft model. These data suggest that EMT predicts HCC sensitivity to EGFR-targeted therapies and that ILK is a novel target to overcome HCC resistance to EGFR inhibition.
...
PMID:Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. 1838 47

Currently, to our knowledge, there are no continuous cell lines derived from estrogen dependent, tamoxifen sensitive spontaneous mouse mammary carcinomas. We describe here the establishment and characterization of a cell line derived from the M05 mouse mammary tumor, LM05-Mix, composed of both an epithelial and a fibroblastic component. From it the respective epithelial LM05-E and fibroblastic LM05-F cell lines were generated by limiting dilution. Immunofluorescence studies confirmed that the epithelial cells were positive for E-cadherin, cytokeratins and vimentin whereas the fibroblastic cells were negative for the epithelial markers and positive for alpha-smooth muscle actin and vimentin. Both cell types expressed estrogen and progesterone receptors, although only the epithelial LM05-E cells were stimulated by estradiol and inhibited by tamoxifen. In the bicellular LM05-Mix cell line estradiol proved to stimulate cell proliferation whereas the response to tamoxifen was dependent on confluency and the degree of epithelial-fibroblastic interactions. The presence of membrane estrogen receptors in both cell types was suggested by the achievement of non-genomic responses to short treatments with estradiol, leading to the phosphorylation of ERK1/2. Finally, cytogenetic studies suggest that these two cell types represent independent cell populations within the tumor and would not be the result of an epithelial-mesenchymal transition. This model presents itself as a valuable alternative for the study of estrogen responsiveness and tamoxifen resistance in the context of epithelial-stromal interactions.
...
PMID:Establishment of an in vitro estrogen-dependent mouse mammary tumor model: a new tool to understand estrogen responsiveness and development of tamoxifen resistance in the context of stromal-epithelial interactions. 1862 96

The effects of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] are mainly mediated by nuclear receptors modulating gene expression. However, there are increasing evidences of nongenomic mechanisms of this hormone associated with kinase- and calcium-activated signaling pathways. In this context, the aim of the present work was to investigate the signaling pathways involved in the mechanism of action of 1,25(OH)(2)D(3) on vimentin phosphorylation in 15-day-old rat testes. Results showed that 1,25(OH)(2)D(3) at concentrations ranging from 1 nM to 1 microM increased vimentin phosphorylation independent of protein synthesis. We also demonstrated that the mechanisms underlying the hormone action involve protein kinase C activation in a phospholipase C-independent manner. Moreover, we showed that the participation of protein kinase A, extracellular regulated protein kinase (ERK), and intra- and extracellular Ca(2+) mediating the effects of 1,25(OH)(2)D(3) on the cytoskeleton. In addition, we investigated the effect of different times of exposure to the hormone on total and phosphoERK1/2 or c-Jun N-terminal kinases 1/2 (JNK1/2) in immature rat testis. Results showed that the total levels of ERK1/2 and JNK1/2 were unaltered from 1 to 15 min exposure to 1,25(OH)(2)D(3). However, the phosphoERK1/2 levels significantly increased at 1 and 5 min 1,25(OH)(2)D(3) treatment. Furthermore, phosphoJNK1 levels were decreased at 10 and 15 min 1,25(OH)(2)D(3) exposure, while phosphoJNK 2 levels were diminished at 5, 10 and 15 min treatment with the hormone. These findings demonstrate that 1,25(OH)(2)D(3) may modulate vimentin phosphorylation through nongenomic Ca(2+)-dependent mechanisms in testis cells.
...
PMID:Vimentin phosphorylation as a target of cell signaling mechanisms induced by 1alpha,25-dihydroxyvitamin D3 in immature rat testes. 1868 49

The growth of LNCaP, a human prostate adenocarcinoma cell line, and MCF-7, a human breast adenocarcinoma cell line, is initially hormone dependent. We previously demonstrated that LNrho0-8 and MCFrho0, derived from LNCaP and MCF-7 by depleting mitochondrial DNA (mtDNA), exhibited hormone-independent growth that led to progressed phenotypes. Here, we demonstrate that LNrho0-8 and MCFrho0 have invasive characters as evaluated by the ability of invasion through the extracellular matrix (ECM) in vitro. In addition, the induction of vimentin and the repression of E-cadherin expression in rho0 cells indicate that they are mesenchymal cells. Since LNrho0-8 and MCFrho0 were derived from epithelial cancer cell lines, LNCaP and MCF-7 must have lost epithelial features and gained the mesenchymal phenotype by epithelial-mesenchymal transition (EMT) during the mtDNA depletion. In the rho0 cell lines, the Raf/MAPK signaling cascade was highly activated together with the expressions of transforming growth factor-beta (TGF-beta) and type I TGF-beta receptor (TGF-betaRI). EMT requires cooperation of TGF-beta signaling with activation of the Raf/MAPK cascade, suggesting that EMT was induced in mtDNA depleted cells resulting in the acquisition of progressive tumor features, such as higher invasiveness and loss of hormone dependent growth. Our results indicate that decreasing mtDNA content induces EMT, enabling the progressive phenotypes observed in cancer.
...
PMID:Progressive tumor features accompany epithelial-mesenchymal transition induced in mitochondrial DNA-depleted cells. 1875 70

In ruminants, interferon-tau (IFNtau) is the maternal recognition signal inhibiting prostaglandin (PG) F2alpha production by endometrial epithelial cells and stimulating interferon-stimulated genes in the stroma. Stromal cells mediate the action of progesterone on epithelial cells during pregnancy. Our working hypothesis is that IFNtau acts as a molecular switch that turns on PGE(2) production in endometrial stromal cells while suppressing PGF2alpha production from epithelial cells. In this report we document immortalization and functional characterization of a bovine stromal cell line from the caruncular region of the endometrium [caruncular stromal cell (CSC)]. Primary stromal cells were immortalized by nucleofection with simian virus 40 large T antigen and integrase. The resulting cell line, CSC, expresses stromal cell-specific vimentin, estrogen, and progesterone receptors, and is amenable for transient transfection. Basal and stimulated production of PGE2 is higher than PGF2alpha and associated with cyclooxygenase (COX) 2 expression. Phorbol myristate acetate (PMA) and IFNtau up-regulate COX2 and PG production in a dose-dependent manner. When added together, low concentrations of IFNtau inhibit PMA-induced COX2 expression; whereas this inhibition is lost at high concentrations. Expression of signal transducer and activator of transcription 1 is induced by IFNtau at all concentrations studied but is not modulated by PMA. Because expression of signal transducer and activator of transcription 1 does not exhibit the biphasic response to IFNtau, we investigated the p38 MAPK pathway using the selective inhibitor SB203580. Inhibition of the p38 MAPK pathway abolishes IFNtau action on PG production. In summary, CSC appears as a good stromal cell model for investigating the molecular mechanisms related to IFNtau action and PG production in the bovine.
...
PMID:Development and characterization of a simian virus 40 immortalized bovine endometrial stromal cell line. 1877 34

Developmental thyroid hormone (TH) deficiency leads to mental retardation and neurological deficits in humans. In this study, congenital hypothyroidism was induced in rats by adding 0.05% 6-propyl-2-thiouracil in the drinking water during gestation and suckling period. This treatment induced hyperphosphorylation of neurofilaments, the neuronal intermediate filament (IF) proteins, of heavy, medium and low molecular weight (NF-H, NF-M and NF-L, respectively) without altering the phosphorylation level of astrocyte IF proteins, glial fibrillary acidic protein (GFAP) and vimentin in cerebral cortex of rats. NF-H was hyperphosphorylated on KSP repeats in the carboxy-terminal tail domain. Furthermore, the immunocontent of GFAP and NF subunits was down-regulated, while vimentin was unaltered both in tissue homogenate and in cytoskeletal fraction of hypothyroid animals. Moreover, we verified the immunocontent of astrocyte glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) as well as activation of mitogen-activated protein kinases (MAPKs) in hypothyroid rats. Results showed that hypothyroidism is associated with decreased GLAST and GLT-1 immunocontent. Additionally, we demonstrated increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation without altering Jun N-terminal kinase (JNK) and p38(MAPK) phosphorylation. However, total JNK levels were down-regulated. Taken together, these results suggest that the thyroid status could modulate the integrity of neuronal cytoskeleton acting on the endogenous NF-associated phosphorylating system and that such effect could be related to glutamate-induced excitotoxicity, as well as ERK1/2 and JNK modulation. These events could be somehow related to the neurological dysfunction described in hypothyroidism.
...
PMID:Congenital hypothyroidism is associated with intermediate filament misregulation, glutamate transporters down-regulation and MAPK activation in developing rat brain. 1884 85


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

---