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)

The 10T1/2-MRF4 fibroblast/myogenic cell system was used to address the following interrelated questions: whether distinct signaling pathways underlie myogenic inhibition by basic fibroblast growth factor (bFGF) and transforming growth factor (TGF)-beta; which of these pathways also up-regulates the fibroblast intermediate conductance calcium-activated potassium channel, FIK, a positive regulator of cell proliferation; and whether FIK up-regulation underlies some or all myogenic inhibitory signaling events. The results show that myogenic inhibition in 10T1/2-MRF4 cells, by both bFGF and TGF-beta, requires activation of the Ras/mitogen-activated protein (MAP) kinase/MAP kinase-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, and resultant FIK up-regulation. We show that FIK is instrumental in MEK-dependent suppression of acetylcholine receptor channel expression but that MEK activation and FIK up-regulation are not essential to suppression of myosin heavy chain and myotube formation. These data indicate that Ras/MEK/ERK induction of FIK is pivotal to regulation of certain myogenic events by both receptor tyrosine kinases and TGF-beta receptor, and this is also the first demonstration of chronic FIK up-regulation by the TGF-beta receptor family. Furthermore, the results define the physiologic signaling requirements for growth factor-stimulated FIK up-regulation, whereas previous work has concentrated on constitutive FIK up-regulation in cells stably transfected with oncoprotein signaling molecules. This study, together with earlier work showing that FIK positively regulates cell proliferation, establishes this member of the IK channel family as a multifunctional, growth factor-regulated signaling molecule.
 ...
PMID:Ras/MEK/ERK Up-regulation of the fibroblast KCa channel FIK is a common mechanism for basic fibroblast growth factor and transforming growth factor-beta suppression of myogenesis. 1078 86

Transformed PDV keratinocytes respond to TGF-beta(1) by stimulating cell motility and invasiveness concomitantly to enhancement of the urokinase-type plasminogen activator (uPA) expression/secretion. Depletion of extracellular signal-regulated kinase (ERK1, 2) proteins by treatment of PDV cells with antisense oligonucleotides reduced basal uPA production and abolished stimulation of uPA secreted levels and cell motility by TGF-beta(1). PD098059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase (MEK), decreased TGF-beta(1)-induced uPA mRNA expression, secreted activity in a dose-dependent manner, and abrogated TGF-beta(1)-stimulated cell motility and invasiveness. PDV-derived dominant-negative RasN17 cell transfectants secreted similar amounts of uPA and exhibited similar invasive abilities as the parental cells or control clones, but were unable to respond to TGF-beta(1) for stimulation of uPA-secreted levels and invasiveness. These results suggest that a Ras/MAPK transduction pathway is involved in the invasive response of transformed keratinocytes to TGF-beta(1).
 ...
PMID:Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-beta(1) in transformed keratinocytes. 1087 38

An avian ortholog of transforming growth factor beta1 (TGFbeta1) is the target-derived factor responsible for the developmental expression of large-conductance Ca(2+)-activated K(+) (K(Ca)) channels in chick ciliary ganglion (CG) neurons developing in vivo and in vitro. Application of TGFbeta1 evokes an acute stimulation of K(Ca) that can be observed immediately after cessation of a 12 hr exposure to this factor, that persists in the presence of protein synthesis inhibitors, and that is therefore mediated by posttranslational events. Here we show that a single 3 hr exposure to TGFbeta1 can also induce long-lasting stimulation of macroscopic K(Ca) that persists for at least 3.5 d after the end of the treatment. In contrast to the acute stimulation, this sustained effect is dependent on the transcription and synthesis of new proteins at approximately the time of TGFbeta1 treatment. However TGFbeta1 does not cause increases in the levels of slowpoke alpha subunit transcripts in CG neurons, suggesting that induction of some other protein or proteins is required for sustained enhancement of macroscopic K(Ca). In addition, application of TGFbeta1 evoked an almost immediate but transient phosphorylation of the mitogen-activated protein kinase Erk in CG neurons. TGFbeta1-evoked Erk activation was blocked by the specific MEK1 inhibitor 2- (2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059). Moreover, application of PD98059 blocked both acute and sustained K(Ca) stimulation evoked by TGFbeta1. These results indicate that TGFbeta1 elicits a biphasic stimulation of K(Ca) via activation of an MEK1-Erk pathway and raise the possibility that other neuronal effects of TGFbeta superfamily members entail Erk activation.
 ...
PMID:Developmental regulation of neuronal KCa channels by TGFbeta 1: transcriptional and posttranscriptional effects mediated by Erk MAP kinase. 1090 98

Increased expression of cyclooxygenase-2 (COX-2) expression has been observed in several human tumor types and in selected animal and cell culture models of carcinogenesis, including lung cancer. Increased expression of COX-2 and production of prostaglandins appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness, and the stimulation of angiogenesis. In the present studies, we found that transforming growth factor beta1 (TGF-beta1) and epidermal growth factor (EGF) synergistically induced the expression of COX-2 and prostaglandin E2 (PGE2) production in mink lung epithelial (Mv1Lu) cells. EGF, but not PDGF or IGF-1, was able to inhibit TGF-beta1-induced apoptosis in Mv1Lu cells and this effect was blocked by NS-398, a selective inhibitor of COX-2 activity, suggesting a possible role for COX-2 in the anti-apoptotic effect of EGF receptor ligands. The combination of TGF-beta1 and EGF also significantly induced COX-2 expression in rat intestinal epithelial (RIE-1) cells and completely prevented sodium butyrate (NaBu)-induced apoptosis. The synergistic induction of COX-2 by TGF-beta1 and EGF was not observed in R1B-L17 cells, a line derived from Mv1Lu cells that lacks the TGF-beta type-I receptor. AG1478, a selective inhibitor of EGF receptor tyrosine kinase activity, completely suppressed the induction of COX-2 expression by either EGF or TGF-beta1+EGF. Also, PD98059, a specific inhibitor of MEK/ERK pathway, and SB203580, a specific inhibitor of p38 MAPK activity, significantly inhibited the induction of COX-2 in response to combined EGF and TGF-beta1. These results suggest an important collaborative interaction of TGF-beta1 and EGF signaling in the induction of COX-2 and prostaglandin production in Mv1Lu cells.
 ...
PMID:Synergistic induction of cyclooxygenase-2 by transforming growth factor-beta1 and epidermal growth factor inhibits apoptosis in epithelial cells. 1093 98

In mouse C3H 10T1/2 cells, we previously reported that TGF-beta1 first delays and later potentiates EGF-induced DNA synthesis corresponding to an inhibition of EGF-induced cyclin D1 expression at t = 13 h. We report here that in accord with DNA synthesis kinetics, TGF-beta1 initially suppresses EGF-induced cyclin D1 expression then later releases the inhibition. Furthermore, TGF-beta1 also first decreases and later potentiates the levels of EGF-activated MEK1/MAPK and PKB, indicating the existence of cross talk between TGF-beta 1- and EGF-activated signal transduction pathways. PD98059, the specific inhibitor of MEK1, significantly blocks EGF-induced DNA synthesis, whereas wortmannin, the PI3K inhibitor, exerts a modest inhibitory effect, which suggests that the activation of MEK1-MAPK pathway plays a major role in EGF-induced DNA synthesis and the activation of PI3K-PKB pathway plays a minor role. Upon examination of mechanisms underlying the cross talk, it was discovered that application of TGF-beta1 triggers a rapid association between Raf-1 and catalytic subunits of PKA, which are reported to be able to inactivate Raf-1 upon activation. Therefore, TGF-beta1 may activate PKA to inhibit the EGF-activated MEK1-MAPK pathway. The wortmannin-sensitive phosphorylation at the thr(389) site is necessary for activation of p70s6K, an important kinase involved in mitogen-stimulated protein synthesis. Although we found that EGF-stimulated p70s6K phosphorylates through a MAPK-dependent and a MAPK-independent (wortmannin-sensitive) pathway, TGF-beta1 failed to block EGF-triggered phosphorylation of p70s6K at thr(389) and thr(421)/ser(424) sites, implying that PKB inhibition by TGF-beta1 may result from inhibition of PDK1 activity instead of inhibition of PI3K activity. These data also suggest that TGF-beta1 may selectively perturb certain EGF-activated MAPK pools.
 ...
PMID:Perturbation of EGF-activated MEK1 and PKB signal pathways by TGF-beta1 correlates with perturbation of EGF-induced cyclin D1 and DNA synthesis by TGF-beta1 in C3H 10T1/2 cells. 1094 24

The decorin gene encodes a proteoglycan with putative structural and regulatory functions whose expression is markedly increased in human mesangial cells (HMC) exposed to high concentrations of glucose (15 to 30 mM). The gene has two promoters (P1 and P2) upstream of two alternative first exons. Transcripts driven by both promoters are present in HMC maintained in 4 mM D-glucose medium. After exposure to 30 mM D-glucose for 7 to 21 d, transcripts driven by P1 are markedly increased, whereas those driven by P2 decrease. Culture in 4 mM D-glucose medium containing transforming growth factor-beta1 (TGF-beta1) (1.25 ng/ml) has the same effect. However, addition of an excess of TGF-beta neutralizing antibody to the 30 mM D-glucose cultures only partly suppressed increased decorin transcription from P1. In transformed HMC transfected with a reporter (p-SAEP) driven by P1 or P2, P1 activity increased twofold on treatment with either 30 mM D-glucose or TGF-beta1 in 4 mM medium. P2 had little activity under any conditions. 5' deletion of P1 showed that basal transcriptional activity lies within the proximal 378 bp, while the major high glucose and TGF-beta response element is located in the -683 to -583-bp region. A putative cAMP response-like sequence (TGACGTTT) lies within this region. Electrophoretic mobility shift assays revealed the same pattern of multiple complexes between oligonucleotides containing this sequence and nuclear proteins extracted from HMC maintained in either 4 or 30 mM D-glucose conditions, but the latter were more prominent. cAMP response element binding protein (CREB) was identified as one transcription factor forming these complexes but other factors remain unidentified. Increased levels of phospho-(Ser 133) CREB were found in HMC exposed to 30 mM D-glucose. High glucose also activated and led to nuclear translocation of p42/44 mitogen-activated protein kinase and p38 mitogen-activated protein kinase, both of which can activate CREB by phosphorylation of serine 133.
 ...
PMID:The decorin high glucose response element and mechanism of its activation in human mesangial cells. 1096 85

The effect of taurine on angiotensin II-induced changes in cell morphology and biochemistry of the cultured neonatal cardiomyocyte was examined. Angiotensin II (1-100 nM) alone caused a slow increase in the surface area of the myocyte accompanied by an induction of the expression of atrial natriuretic peptide (ANP) and an upregulation of transforming growth factor beta(1) gene (TGF-beta(1)). The signaling pathway of angiotensin II (1-100 nM) was found to proceed through protein kinase C and the rapid activation of mitogen-activated protein (MAP) kinases. Pretreatment of the myocyte with taurine (20 mM) in the absence of angiotensin II had no visible effect on cell size or growth rate. However, the cells that were pretreated with taurine (20 mM) for 24 h exhibited reduced responsiveness to angiotensin II (100 nM) relative to surface cell area enlargement and the upregulation of the late and growth factor genes(ANP, TGF-beta(1)). Angiotensin II-mediated activation of the MAP kinases (extracellular signal-regulated protein kinase 1/2: ERK1/2) was not blocked by taurine. Taurine reduced the phosphorylation of a 29-kDa protein, a reaction which was enhanced by angiotensin II and appears to involve protein kinase C step. The results indicate that taurine is an effective inhibitor of certain aspects of angiotensin II action.
 ...
PMID:Taurine attenuates hypertrophy induced by angiotensin II in cultured neonatal rat cardiac myocytes. 1097 17

Ras-transformed intestinal epithelial cells are resistant to the growth inhibitory actions of TGFbeta and have a marked decrease in expression of the TGFbeta type II receptor (TGFbetaRII). Rat intestinal epithelial cells (RIE) were stably transfected with activated Ras, Sos and Raf constructs and tested for expression of TGFbetaRII and sensitivity to growth inhibition by TGFbeta. The parental RIE line and the RIE-Raf cells were non-transformed in morphology and were sensitive to TGFbeta (70-90% inhibited). In contrast, the RIE-Ras and RIE-Sos lines were transformed, resistant to TGFbeta and expressed 5- to 10-fold decreased levels of the TGFbetaRII mRNA and protein. Cyclin D1 protein expression was repressed by TGFbeta treatment in parental RIE and RIE-Raf cells, whereas levels of cyclin D1 in RIE-Ras and RIE-Sos cells remained unchanged. Treatment of RIE-Ras cells with 25 microM farnesyl transferase inhibitor, FTI L739,749, for 48 hours restored expression of TGFbetaRII to levels equivalent to control cells. In addition, treatment of RIE-Ras cells for 48 hours with PD-98059, a specific MAPKK inhibitor, also increased expression of TGFbetaRII to control levels. Collectively these results suggest that downregulation of TGFbetaRII and loss of sensitivity to growth inhibition by TGFbeta in Ras-transformed intestinal epithelial cells is not mediated exclusively by the conventional Ras/Raf/MAPKK/MAPK pathway. However, activation of MAPK, perhaps by an alternate Ras effector pathway, appears to be necessary for Ras-mediated downregulation of TGFbetaRII.
 ...
PMID:Ras-mediated suppression of TGFbetaRII expression in intestinal epithelial cells involves Raf-independent signaling. 1100 70

c-Raf-1 is a major effector of Ras proteins, responsible for activation of the ERK MAP kinase pathway and a critical regulator of both normal growth and oncogenic transformation. Using an inducible form of Raf in MDCK cells, we have shown that sustained activation of Raf alone is able to induce the transition from an epithelial to a mesenchymal phenotype. Raf promoted invasive growth in collagen gels, a characteristic of malignant cells; this was dependent on the operation of an autocrine loop involving TGFbeta, whose secretion was induced by Raf. TGFbeta induced growth inhibition and apoptosis in normal MDCK cells: Activation of Raf led to inhibition of the ability of TGFbeta to induce apoptosis but not growth retardation. ERK has been reported previously to inhibit TGFbeta signaling via phosphorylation of the linker region of Smads, which prevents their translocation to the nucleus. However, we found no evidence in this system that ERK can significantly influence the function of Smad2, Smad3, and Smad4 at the level of nuclear translocation, DNA binding, or transcriptional activation. Instead, strong activation of Raf caused a broad protection of these cells from various apoptotic stimuli, allowing them to respond to TGFbeta with increased invasiveness while avoiding cell death. The Raf-MAP kinase pathway thus synergizes with TGFbeta in promoting malignancy but does not directly impair TGFbeta-induced Smad signaling.
 ...
PMID:Raf induces TGFbeta production while blocking its apoptotic but not invasive responses: a mechanism leading to increased malignancy in epithelial cells. 1104 Feb 15

Transforming growth factor (TGF)-beta1 has been implicated in vascular healing responses after mechanical injury. Using cultured rat aortic smooth muscle cells (RASMC), we examined the hypothesis that production and secretion of thrombospondin (TSP) contributes to TGF-beta1-induced proliferation. We found that TGF-beta1 enhanced production and secretion of TSP, with peak levels of secreted TSP observed 24 h after treatment. RASMC treated with TGF-beta1 secreted a mitogenic activity that was transferable in conditioned media and partially inhibited by C6.7, a monoclonal anti-TSP antibody. Exogenous TSP stimulated a proliferative response, with maximal [(3)H]thymidine incorporation occurring 24 h earlier than maximal [(3)H]thymidine incorporation in response to TGF-beta1-treatment. Pretreatment with C6.7 or polyclonal anti-TSP neutralizing antibodies inhibited TGF-beta1-induced proliferation of RASMC. Proliferative responses to TGF-beta1 were also inhibited by pretreatment with an anti-beta(3) integrin monoclonal blocking antibody (F11), RGD peptides, and the anti-alpha(v)beta(3) disintegrin echistatin. Treatment with TSP and TGF-beta1 increased c-Jun NH(2)-terminal kinase (JNK)1 activity, with peak effects observed at 15 min and 4 h, respectively. Treatment with C6.7 or F11 inhibited TGF-beta-induced activation of JNK1. In summary, these studies support the hypothesis that TGF-beta-induced JNK1 activation and proliferation of RASMC require secretion of TSP and ligation of alpha(v)beta(3)-integrins.
 ...
PMID:Autocrine thrombospondin partially mediates TGF-beta1- induced proliferation of vascular smooth muscle cells. 1104 49


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