Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cells from patients with MDS-derived AML display heterogeneous proliferative responses to transforming growth factor beta (TGF beta). We analyzed growth inhibition and SMAD2 phosphorylation by TGF beta in CD34+ cells from nine patients, as compared to normal controls. While TGF beta consistently inhibited thymidine incorporation of normal cells (41% of control, P < 0.05), cells from patients with AML were growth-inhibited in only four of seven cases (40%), whereas TGF beta stimulated thymidine incorporation in the three other samples (166%). Remarkably, TPO reverted the stimulatory effect of TGF beta to profound growth inhibition. Upon exposure to TGF beta, SMAD2 protein was phosphorylated in normal CD34+ cells (n = 3), CD34+ leukemic blasts from all examined patients with AML (n = 4), and in the myeloid leukemic cell lines M-07e and HEL. TGF beta inhibited TPO-mediated thymidine incorporation, cell proliferation and survival in all samples analyzed. In M-07e cells and CD34+ cells from healthy donors, this inhibition was enhanced by an antagonist of JAK2 (AG490), but not a MEK-1 antagonist (PD098059). Conversely, in CD34+ cells from a patient with AML, both AG490 and PD098059 significantly enhanced TGF beta-mediated suppression of TPO-induced thymidine incorporation. Thus, in MDS-derived AML, altered responses to TGF beta may be due to defects downstream of SMAD2 and may involve MAPK activation.
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PMID:TGF beta-induced SMAD2 phosphorylation predicts inhibition of thymidine incorporation in CD34+ cells from healthy donors, but not from patients with AML after MDS. 1141 81

The interplay of fibroblast growth factor (FGF) and nodal signaling in the Xenopus gastrula marginal zone specifies distinct populations of presumptive mesodermal cells. Cells in the vegetal marginal zone, making up the presumptive leading edge mesoderm, are exposed to nodal signaling, as evidenced by SMAD2 activation, but do not appear to be exposed to FGF signaling, as evidenced by the lack of MAP kinase (MAPK) activation. However, in the animal marginal zone, activation of both SMAD2 and MAPK occurs. The differential activation of these two signaling pathways in the marginal zone results in the vegetal and animal marginal zones expressing different genes at gastrulation, and subsequently having different fates, with the vegetal marginal zone contributing to ventral mesoderm (e.g. ventral blood island) and the animal marginal zone giving rise to dorsal fates (e.g. notochord and somite). We report here the cloning of a cDNA encoding a novel nuclear protein, Xmenf, that is expressed in the vegetal marginal zone. The expression of Xmenf is induced by nodal signaling and negatively regulated by FGF signaling. Results from animal cap studies indicate that Xmenf plays a role in the pathway of ventral mesoderm induction in the vegetal marginal zone.
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PMID:The nodal target gene Xmenf is a component of an FGF-independent pathway of ventral mesoderm induction in Xenopus. 1235 Nov 69

Both activin and GnRH can independently stimulate expression of the FSHbeta subunit gene. In this study, we used the gonadotrope-derived LbetaT2 cell line to investigate the potential interaction between activin and GnRH in regulating the transcriptional activity of the rat FSHbeta gene promoter. Activin A and GnRH synergistically enhanced rat FSHbeta transcriptional activity. Overexpression of SMAD3 (mediator of decapentaplegic-related protein 3), but not of SMAD2, increased transcriptional activation of the rat (r) FSHbeta gene promoter, which was further enhanced by the combined overexpression of SMAD3 and 4 (3+4). The stimulatory effects of SMAD3 overexpression were localized to -472/-256 of the rFSHbeta gene promoter, and activin- and GnRH-responsive proteins were shown to bind to region -284/-252. Sequence analysis identified a consensus palindromic SMAD-binding site at -266/-259 of the rFSHbeta gene promoter. Mutation of two bases located in the center of this palindrome effectively abrogated SMAD4 binding, markedly reduced SMAD3 and 3+4 stimulation of the rFSHbeta gene promoter, and significantly decreased the synergistic enhancement of promoter activity by both activin A and GnRH, and SMAD3 and GnRH. Blockade of the MAPK-signaling pathway did not significantly affect the response to combined stimulation with activin and GnRH. In contrast, interference with SMAD3 signaling caused a significant reduction in activin and GnRH synergy. The results indicate that SMAD3 plays an important role in the synergistic effects of activin and GnRH and demonstrate that this synergy is mediated by a palindromic cis-element located at -266/-259 of the rFSHbeta gene promoter.
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PMID:Synergy between activin A and gonadotropin-releasing hormone in transcriptional activation of the rat follicle-stimulating hormone-beta gene. 1537 86

Hippocampal granule cells self-renew throughout life, whereas their cerebellar counterparts become post-mitotic during early postnatal development, suggesting that locally acting, tissue-specific factors may regulate the proliferative potential of each cell type. Confirming this, we show that conditioned medium from hippocampal cells (CM(Hippocampus)) stimulates proliferation in cerebellar cultures and, vice versa, that mitosis in hippocampal cells is inhibited by CM(Cerebellum). The anti-proliferative effects of CM(Cerebellum) were accompanied by increased expression of the cyclin-dependent kinase inhibitors p21 and p27, as well as markers of neuronal maturity/differentiation. CM(Cerebellum) was found to contain peptide-like factors with distinct anti-proliferative/differentiating and neuroprotective activities with differing chromatographic properties. Preadsorption of CM(Cerebellum) with antisera against candidate cytokines showed that TGFbeta2 and BDNF could account for the major part of the anti-proliferative and pro-differentiating activities, an interpretation strengthened by studies involving treatment with purified TGFbeta2 and BDNF. Interference with signaling pathways downstream of TGFbeta and BDNF using dominant-negative forms of their respective receptors (TGFbeta2-RII and TRKB) or of dominant-negative forms of SMAD3 and co-SMAD4 negated the anti-proliferative/differentiating actions of CM(Cerebellum). Treatment with CM(Cerebellum) caused nuclear translocation of SMAD2 and SMAD4, and also transactivated a TGFbeta2-responsive gene. BDNF actions were shown to depend on activation of ERK1/2 and to converge on the SMAD signaling cascade, possibly after stimulation of TGFbeta2 synthesis/secretion. In conclusion, our results show that the regulation of hippocampal cell fate in vitro is regulated through an interplay between the actions of BDNF and TGFbeta.
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PMID:SMAD pathway mediation of BDNF and TGF beta 2 regulation of proliferation and differentiation of hippocampal granule neurons. 1595 11

Complex cellular networks regulate regeneration, detoxification and differentiation of hepatocytes. By combining experimental data with mathematical modelling, systems biology holds great promises to elucidate the key regulatory mechanisms involved and predict targets for efficient intervention. For the generation of high-quality quantitative data suitable for mathematical modelling a standardised in vitro system is essential. Therefore the authors developed standard operating procedures for the preparation and cultivation of primary mouse hepatocytes. To reliably monitor the dynamic induction of signalling pathways, the authors established starvation conditions and evaluated the extent of starvation-associated stress by quantifying several metabolic functions of cultured primary hepatocytes, namely activities of glutathione-S-transferase, glutamine synthetase, CYP3A as well as secretion of lactate and urea into the culture medium. Establishment of constant metabolic activities after an initial decrease compared with freshly isolated hepatocytes showed that the cultured hepatocytes achieve a new equilibrium state that was not affected by our starving conditions. To verify the highly reproducible dynamic activation of signalling pathways in the in vitro system, the authors examined the JAK-STAT, SMAD, PI3 kinase, MAP kinase, NF-kappaB and Wnt/beta-catenin signalling pathways. For the induction of gp130, JAK1 and STAT3 phosphorylation IL6 was used, whereas TGFbeta was applied to activate the phosphorylation of SMAD1, SMAD2 and SMAD3. Both Akt/PKB and ERK1/2 phosphorylation were stimulated by the addition of hepatocyte growth factor. The time-dependent induction of a pool of signalling competent beta-catenin was monitored in response to the inhibition of GSK3beta. To analyse whether phosphorylation is actually leading to transcriptional responses, luciferase reporter gene constructs driven by multiple copies of TGFbeta-responsive motives were applied, demonstrating a dose-dependent increase in luciferase activity. Moreover, the induction of apoptosis by the TNF-like cytokine Fas ligand was studied in the in vitro system. Thus, the mouse hepatocyte in vitro system provides an important basis for the generation of high-quality quantitative data under standardised cell culture conditions that is essential to elucidate critical hepatocellular functions by the systems biology approach.
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PMID:Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways. 1718 5

The TGF-beta signaling pathways are implicated in cancer. Cysteine cathepsins can contribute to the carcinogenic potential of tumor cells. The aim of this study was to investigate the regulation of cysteine cathepsin expression by TGF-beta1 and the functional implications in tumor cells. We found an upregulation of cathepsin B (CathB, 2- to 5-fold) in different myeloid tumor cells (THP-1, MonoMac-1, MonoMac-6) after incubation with TGF-beta1. No upregulation was found in monocytes, and there was suppression of CathB expression in epithelial tumor cells (A549). Increased cathepsin B activity led to enhanced carcinogenic potential, which was reflected by increased migration and invasion of the cells and resistance to inhibitor-induced apoptosis. Analysis of the TGF-beta signaling pathways showed no alterations in TGF-beta/BMP receptor expression or SMAD2/3 phosphorylation, and no influence of MAP kinase pathways. However, a reduction in SMAD1 expression was detected. The lack of BMP action on cysteine cathepsin expression in myeloid tumor cells, but not in epithelial tumor cells, suggests a defect in the Smad1/Smad5 pathway. We located a related TGF-beta1-responsive element within the first intron of the CathB gene. In conclusion, alterations in the TGF-beta1 signaling pathway lead to upregulation of CathB, which contributes to the carcinogenic potential of tumor cells.
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PMID:Increased carcinogenic potential of myeloid tumor cells induced by aberrant TGF-beta1-signaling and upregulation of cathepsin B. 1755 11

TGF-beta1 and its target gene encoding plasminogen activator inhibitor-1 (PAI-1) are major causative factors in the pathology of tissue fibrosis and vascular disease. The increasing complexity of TGF-beta1 action in the cardiovascular system requires analysis of specific TGF-beta1-initiated signaling events that impact PAI-1 transcriptional regulation in a physiologically-relevant cell system. TGF-beta1-induced PAI-1 expression in both primary cultures and in an established line (R22) of vascular smooth muscle cells (VSMC) was completely blocked by inhibition of epidermal growth factor receptor (EGFR) activity or adenoviral delivery of a kinase-dead EGFR(K721A) construct. TGF-beta1-stimulated PAI-1 expression, moreover, was preceded by EGFR phosphorylation on Y845 (a src kinase target residue) and required pp60(c-src) activity. Infection of VSMC with an adenovirus encoding the EGFR(Y845F) mutant or transfection with a dominant-negative pp60(c-src) (DN-Src) expression vector effectively decreased TGF-beta1-stimulated, but not PDGF-induced, PAI-1 expression implicating the pp60(c-src) phosphorylation site EGFR(Y845) in the inductive response. Consistent with these findings, TGF-beta1 failed to induce PAI-1 synthesis in src kinase-deficient (SYF(-/-/-)) fibroblasts and reexpression of a wild-type pp60(c-src) construct in SYF(-/-/-) cells rescued the PAI-1 response to TGF-beta1. TGF-beta1-induced EGFR activation, but not SMAD2 activation, moreover, was virtually undetectable in SYK(-/-/-) fibroblasts in comparison to wild type (SYK(+/+/+)) counterparts, confirming an upstream signaling role of src family kinases in EGFR(Y845) phosphorylation. Genetic EGFR deficiency or infection of VSMCs with EGFR(K721A) virtually ablated TGF-beta1-stimulated ERK1/2 activation as well as PAI-1 expression but not SMAD2 phosphorylation. Transient transfection of a dominant-negative RhoA (DN-RhoA) expression construct or pretreatment of VSMC with C3 transferase (a Rho inhibitor) or Y-27632 (an inhibitor of p160ROCK, a downstream effector of Rho) also dramatically attenuated the TGF-beta1-initiated PAI-1 inductive response. In contrast to EGFR pathway blockade, interference with Rho/ROCK signaling effectively inhibited TGF-betaR-mediated SMAD2 phosphorylation and nuclear accumulation. TGF-beta1-stimulated SMAD2 activation, moreover, was not sufficient to induce PAI-1 expression in the absence of EGFR signaling both in VSMC and mouse embryonic fibroblasts. Thus, two distinct pathways involving the EGFR/pp60(c-src)/MEK-ERK pathway and Rho/ROCK-dependent SMAD2 activation are required for TGF-beta1-induced PAI-1 expression in VSMC. The identification of such novel interactions between two TGF-beta1-activated signaling networks that specifically impact PAI-1 transcription in VSMC may provide therapeutically-relevant targets to manage the pathophysiology of PAI-1-associated cardiovascular/fibrotic diseases.
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PMID:TGF-beta1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60(c-src)/EGFR(Y845) and Rho/ROCK signaling. 1825 94

Overexpression of plasminogen activator inhibitor-1 (SERPINE1, PAI-1), the major physiological inhibitor of pericellular plasmin generation, is a significant causative factor in the progression of vascular disorders (e.g. arteriosclerosis, thrombosis, perivascular fibrosis) as well as a biomarker and a predictor of cardiovascular-disease associated mortality. PAI-1 is a temporal/spatial regulator of pericellular proteolysis and ECM accumulation impacting, thereby, vascular remodeling, smooth muscle cell migration, proliferation and apoptosis. Within the specific context of TGF-beta1-initiated vascular fibrosis and neointima formation, PAI-1 is a member of the most prominently expressed subset of TGF-beta1-induced transcripts. Recent findings implicate EGFR/pp60c-src-->MEK/ERK1/2 and Rho/ROCK-->SMAD2/3 signaling in TGF-beta1-stimulated PAI-1 expression in vascular smooth muscle cells. The EGFR is a direct upstream regulator of MEK/ERK1/2 while Rho/ROCK modulate both the duration of SMAD2/3 phosphorylation and nuclear accumulation. E-box motifs (CACGTG) in the PE1/PE2 promoter regions of the human PAI-1 gene, moreover, are platforms for a MAP kinase-directed USF subtype switch (USF-1-->USF-2) in response to growth factor addition suggesting that the EGFR-->MEK/ERK axis impacts PAI-1 expression, at least partly, through USF-dependent transcriptional controls. This paper reviews recent data suggesting the essential cooperativity among the EGFR-->MAP kinase cascade, the Rho/ROCK pathway and SMADs in TGF-beta1-initiated PAI-1 expression. The continued clarification of mechanistic controls on PAI-1 transcription may lead to new targeted therapies and clinically-relevant options for the treatment of vascular diseases in which PAI-1 dysregulation is a major underlying pathogenic feature.
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PMID:Integration of non-SMAD and SMAD signaling in TGF-beta1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells. 1913 20

The serotonin transporter (SERT) gene has been proposed as a candidate gene responsible for the sudden infant death syndrome (SIDS). In this study, for the first time we obtained a SERT-knockout (KO) mouse model which reproduces SIDS phenotype. SERT-KO mice were generated by mating SERT(Cre/+) heterozygous mice. The SERT-KO mouse embryos at the pre-natal stage E18.5 were lacking of SERT mRNA and protein expression in the heart. A premature death of 75% of SERT-KO mice occurred in the first week after birth. LacZ staining of whole mounts and tissue sections of the heart from SERT(Cre/+);ROSA26R adult mice and E18.5 embryos demonstrated a marked localized expression of SERT in the right ventricle, the conal region, the vasculature, the atrial septum, the ventricular valves, and the sinoatrial node of the conduction system. These data suggest a cardiac phenotype for the sudden death of SERT-KO mice. Histological analysis of heart sections showed that SERT-KO mice develop cardiac fibrosis. Increased collagen accumulation in the myocardium and the valvular and perivascular regions, and enhanced expression of alpha-smooth muscle actin were detected in the heart of SERT-KO mice versus wild-type (WT) mice. Interestingly, higher expression levels of the 5-HT2A receptor and increased levels of phospho-SMAD2/3 and phospho-ERK1/2 were detected in SERT-KO mouse heart versus WT mice. Overall, our findings provide i) new insights into the role of SERT gene in SIDS, and ii) the first in vivo validation of the molecular mechanism involving the activation of TGF-beta1 signalling in the cardiac fibrosis.
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PMID:Serotonin transporter gene deficiency is associated with sudden death of newborn mice through activation of TGF-beta1 signalling. 1964 88

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.
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PMID:Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. 2019 48


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