Gene/Protein Disease Symptom Drug Enzyme Compound
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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 expression of syndecan-1 generally appears down-regulated in human cancers and experimental models, whereas transfectional expression of syndecan-1 in cancer cells has been shown to inhibit aspects of their malignant behavior. To clarify how reduced levels of syndecan-1 may confer enhanced invasiveness, we transfected human ovarian cancer cell line HRA with antisense (AS) syndecan-1 oligodeoxynucleotide (ODN) and compared the properties of transfected cells to those of parental cells or sense (S) syndecan-1 cells. Here, we show: 1) there was lower proliferation in the AS syndecan-1 cells compared to controls (parental HRA cells and S syndecan-1 cells) when cells were incubated with HB-GFs (HB-EGF, HGF, or FGF2); 2) transfection of HRA cells with a syndecan-1 AS ODN enhanced the increase in HB-GF-dependent invasiveness; 3) in contrast, IGF-I stimulated cell proliferation and invasion, irrespective of whether cells were transfected with the AS syndecan-1 gene; 4) IGF-I stimulated ERK1/2 activation and uPA expression in both the control and AS cells, whereas the net effect of the reduction of syndecan-1 is to shift the HB-GF dose-response curve to the right; 5) the AS cells reduced activation and up-regulation of ERK1/2 phosphorylation and uPA expression, respectively, in response to HB-GFs; and 6) in comparison with early stage ovarian cancer tissues, there was a 3-fold decrease in syndecan-1 mRNA levels in advanced stage tissues. Taken together, these data suggest that decreased syndecan-1 expression may be associated with enhanced cell invasion possibly through the uPA-independent mechanism.
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PMID:Reduced syndecan-1 expression stimulates heparin-binding growth factor-mediated invasion in ovarian cancer cells in a urokinase-independent mechanism. 1601 29

Childhood hypothyroidism causes growth arrest with delayed ossification and growth-plate dysgenesis, whereas thyrotoxicosis accelerates ossification and growth. Thyroid hormone (T(3)) regulates chondrocyte proliferation and is essential for hypertrophic differentiation. Fibroblast growth factors (FGFs) are also important regulators of chondrocyte proliferation and differentiation, and activating mutations of FGF receptor-3 (FGFR3) cause achondroplasia. We investigated the hypothesis that T(3) regulates chondrogenesis via FGFR3 in ATDC5 cells, which undergo a defined program of chondrogenesis. ATDC5 cells expressed two FGFR1, four FGFR2, and one FGFR3 mRNA splice variants throughout chondrogenesis, and expression of each isoform was stimulated by T(3) during the first 6-12 d of culture, when T(3) inhibited proliferation by 50%. FGFR3 expression was also increased in cells treated with T(3) for 21 d, when T(3) induced an earlier onset of hypertrophic differentiation and collagen X expression. FGFR3 expression was reduced in growth plates from T(3) receptor alpha-null mice, which exhibit skeletal hypothyroidism, but was increased in T(3) receptor beta(PV/PV) mice, which display skeletal thyrotoxicosis. These findings indicate that FGFR3 is a T(3)-target gene in chondrocytes. In further experiments, T(3) enhanced FGF2 and FGF18 activation of the MAPK-signaling pathway but inhibited their activation of signal transducer and activator of transcription-1. FGF9 did not activate MAPK or signal transducer and activator of transcription-1 pathways in the absence or presence of T(3). Thus, T(3) exerted differing effects on FGFR activation during chondrogenesis depending on which FGF ligand stimulated the FGFR and which downstream signaling pathway was activated. These studies identify novel interactions between T(3) and FGFs that regulate chondrocyte proliferation and differentiation during chondrogenesis.
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PMID:Thyroid hormones regulate fibroblast growth factor receptor signaling during chondrogenesis. 1615 Sep 8

Fibroblast growth factors (FGFs) are soluble ligands important for embryonic patterning, limb and brain development, and stem cell proliferation. They activate specific receptors (FGFR) to elicit changes in gene expression and cellular responses such as proliferation, differentiation, and survival, but the extent to which these pleiotropic responses are driven by FGF concentration gradients has not been systematically addressed. Here, we show that a single cell type exhibits divergent, even opposing, responses to a single FGF dependent on the exposure concentration, and that this is controlled by differential signaling with specific negative feedback inhibition. Low concentrations of FGF2 stimulate survival and differentiation but actively inhibit proliferation while intermediate concentrations stimulate proliferation in the presence of serum but apoptosis in its absence. Intriguingly, high concentrations reverse the proliferation and apoptosis effects, and mirror the low concentration effects: inhibition of proliferation and stimulation of survival and differentiation. By screening for activation of sampled signaling intermediates across the FGF2 concentration range in fibroblasts, we show that the peak in proliferation and apoptosis correlates with abrupt activation of FRS-2 and Erk that is specifically down-regulated by high concentrations of FGF2, a pattern that contrasts with an incremental increase in activation of p38 MAP kinase and the FGFR itself, across the FGF2 concentration range. Whilst proliferation stimulated by FGF2 was dependent on p38 MAP kinase, apoptosis stimulated by proliferative concentrations of FGF2 under serum-free conditions was, in contrast, dependent on Erk MAP kinase. These findings indicate that FGF exposure concentration precisely controls intracellular signaling and cellular responses to the growth factor, and have important implications for understanding how FGF gradients influence cell proliferation, survival, and differentiation during processes such as limb development.
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PMID:Ligand concentration is a driver of divergent signaling and pleiotropic cellular responses to FGF. 1615 40

Sodium nitroprusside (SNP), a nitric oxide (NO) donor and a nitrovasodilator drug used for patients with hypertensive crisis, has been shown to promote angiogenesis. However, direct evidence showing the involvement of NO in the SNP-induced angiogenesis is not available. Accordingly, we assessed whether NO generated from SNP-stimulated ovine fetoplacental artery endothelial (OFPAE) cell proliferation via activation of mitogen-activated protein kinase 3/1 (MAPK3/1, also termed ERK1/2). We observed that SNP dose dependently stimulated (P < 0.05) cell proliferation with a maximal effect at 1 microM and that SNP rapidly (<or=15 min) phosphorylated (P < 0.05) MAPK3/1 but not v-akt murine thymoma viral oncogene homolog 1 (AKT1). Treatment of cells with SNP caused a rapid increase in NO levels in media. These increased NO levels were inhibited (P < 0.05) by 2-phenyl-4,4,5,5 tetramethylimidazoline-1-oxyl 3-oxide (PTIO), a NO scavenger. The SNP-induced cell proliferation and MAPK3/1 phosphorylation were attenuated (P < 0.05) by both PTIO and PD98059, a specific mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2, also termed MEK1/2) inhibitor. Using a semiquantitative RT-PCR analysis, we also showed that up to 12 h of treatment, SNP and N(G)-monomethyl-L-arginine (L-NMMA, a NOS inhibitor) did not alter mRNA expression of VEGF, FGF2, and their major receptors in OFPAE cells. The SNP's stimulatory effects on OFPAE cell proliferation and MAPK3/1 activation were confirmed in a human placental artery endothelial (HPAE) cell line. These data indicate that exogenous NO generated from SNP is able to stimulate fetoplacental artery endothelial cell proliferation at least partly via activation of the MAP2K1/2/MAPK3/1 cascade. These data also suggest that SNP could potentially be used to modulate placental angiogenesis.
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PMID:Exogenous nitric oxide stimulates cell proliferation via activation of a mitogen-activated protein kinase pathway in ovine fetoplacental artery endothelial cells. 1625 2

In this study, DNA synthesis, phosphorylation of ERK1/2 and CREB proteins, as well as induction of c-Fos protein, were examined in rat adrenocortical, glomerulosa and fasciculata/reticularis cells, as well as in the Y1 cell line. We found that FGF2 was mitogenic only in glomerulosa cells and although ACTH did not activate ERK1/2, it did activate CREB protein, indicating efficient transduction of signals initiated in the ACTH receptors of rat adrenocortical cells. The FGF2 activated ERK1/2 in rat adrenal cells by a mechanism that might be modulated by upstream PKA pathway phosphorylation of MEK and despite the nonmitogenic effect of ACTH on rat adrenal cells it effectively induces c-Fos protein. The results presented herein describe distinct differences between the ACTH and FGF2 signal transduction mechanisms seen in adrenocortical cells and those observed in the Y1 cell line, indicating that, in vitro, ACTH blockage of the mitogenic effect occurs in normal adrenal cells after induction of c-Fos protein.
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PMID:Differences between the growth regulatory pathways in primary rat adrenal cells and mouse tumor cell line. 1628 4

Fibroblast growth factor (FGF) signaling is thought to play a role in germ cell behavior. FGF2 has been reported to be a mitogen for primordial germ cells in vitro, whilst combinations of FGF2, steel factor and LIF cause cultured germ cells to transform into permanent lines of pluripotent cells resembling ES cells. However, the actual function of FGF signaling on the migrating germ cells in vivo is unknown. We show, by RT-PCR analysis of cDNA from purified E10.5 germ cells, that germ cells express two FGF receptors: Fgfr1-IIIc and Fgfr2-IIIb. Second, we show that FGF-mediated activation of the MAP kinase pathway occurs in germ cells during their migration, and thus they are potentially direct targets of FGF signaling. Third, we use cultured embryo slices in simple gain-of-function experiments, using FGF ligands, to show that FGF2, a ligand for FGFR1-IIIc, affects motility, whereas FGF7, a ligand for FGFR2-IIIb, affects germ cell numbers. Loss of function, using a specific inhibitor of FGF signaling, causes increased apoptosis and inhibition of cell shape change in the migrating germ cells. Lastly, we confirm in vivo the effects seen in slice cultures in vitro, by examining germ cell positions and numbers in embryos carrying a loss-of-function allele of FGFR2-IIIb. In FGFR2-IIIb(-/-) embryos, germ cell migration is unaffected, but the numbers of germ cells are significantly reduced. These data show that a major role of FGF signaling through FGFR2-IIIb is to control germ cell numbers. The data do not discriminate between direct and indirect effects of FGF signaling on germ cells, and both may be involved.
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PMID:The roles of FGF signaling in germ cell migration in the mouse. 1629 96

Supplementation with exogenous growth factors such as fibroblast growth factors (FGFs) is essential for anchorage-independent growth of the SW-13 human adrenal adenocarcinoma cell line. We have found that SW-13 cells express mRNAs for FGFRs 1, 3, and 4, but not FGFR2. To assess the roles of individual FGFRs, in anchorage-independent growth, we determined the effects of down-regulation of each FGFR on FGF2- and FGF4-mediated soft agar colony formation in these cells. Using RNAi strategies we found that knockdown of either FGFR1 or FGFR3 leads to inhibition of FGF2- or FGF4-induced soft agar clonogenicity without affecting that induced by heregulin beta1. However, this inhibition is independent of ERK1/2 activation as levels of FGF-induced phospho-ERK 1/2 remain unchanged upon knockdown of either FGFR1 or FGFR3. Conversely, RNAi-mediated knockdown of FGFR4 appeared to have no significant effect on either FGF2- or FGF4-induced anchorage-independent colony formation, or ERK1/2 phosphorylation. These results suggest that constitutive levels of both FGFR1 and FGFR3, but not FGFR4 are essential for FGF-stimulated anchorage-independent growth of SW-13 cells.
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PMID:siRNA mediated knockdown of fibroblast growth factor receptors 1 or 3 inhibits FGF-induced anchorage-independent clonogenicity but does not affect MAPK activation. 1668 73

We have isolated the Xenopus ortholog of ADAMTS1 (a disintegrin and metalloprotease with thrombospondin motifs), XADAMTS1, which is expressed in the presumptive ectoderm, then the Spemann organizer, and later in the trunk organizer region and posterior ectoderm in the Xenopus embryo. We show that, when overexpressed in the dorsal marginal zone or in the anterior ectoderm by mRNA injection, XADAMTS1 inhibits gastrulation or generates embryos with an enlarged cement gland, respectively. XADAMTS1 also reduces the expression of Xbra in both whole embryos and FGF-treated animal caps. These effects of XADAMTS1 are likely to be due to its inhibition of the Ras-MAPK cascade because XADAMTS1 inhibits the phosphorylation of ERK by FGF4 in animal caps. Deletion analysis of XADAMTS1 revealed that a combination of the signal peptide and the C-terminal region containing the thrombospondin type 1 repeats is necessary and sufficient for this function, whereas the metalloprotease domain is dispensable. In addition, loss-of-function analysis with antisense morpholino oligos showed that knockdown of XADAMTS1 sensitizes animal caps to Xbra induction by FGF2. These data suggest that secreted XADAMTS1 negatively modulates FGF signaling in the Xenopus embryo.
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PMID:Xenopus ADAMTS1 negatively modulates FGF signaling independent of its metalloprotease activity. 1669 49

The mouse Y1 adrenocortical tumor cell line is highly responsive to FGF2-(Fibroblast Growth Factor 2) and possesses amplified and over-expressed c-Ki-ras proto-oncogene. We previously reported that this genetic lesion leads to high constitutive levels of activation of the c-Ki-Ras-GTP-->PI3K-->Akt signaling pathway (Forti et al. 2002). On the other hand, activation levels of another important pathway downstream of c-Ki-Ras-GTP, namely, Raf-->MEK-->ERK, remain strictly dependent on FGF2 stimulation (Rocha et al. 2003). Here we show that, first, FGF2 transiently up-regulates the c-Ki-Ras-GTP-->PI3K-->Akt pathway, in spite of its high basal levels. Second, c-Ki-Ras-GTP transient up-regulation likely underlies activation of the ERK1/2 pathway by FGF2. Third, c-Ki-Ras-GTP high basal levels suppress activation of the c-H-Ras onco-protein. But, Y1 cells, expressing dominant negative mutant RasN17, display a rapid and transient up-regulation of c-H-Ras-GTP upon FGF2 treatment. Elucidation of FGF2-signaling pathways in Y1 tumor cells can uncover new targets for drug development of interest in cancer therapy.
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PMID:c-Ki-ras oncogene amplification and FGF2 signaling pathways in the mouse Y1 adrenocortical cell line. 1671 May 63

Endothelial cells line the blood vessel and precursor endothelial cells appear to have a pivotal effect on the organ formation of the heart, the embryonic development of the kidney, and the liver. Several growth factors including the fibroblast growth factors (FGF) seem to be involved in these processes. Ligands such as basic FGF produced and secreted by endothelial cells may also coordinate cellular migration, differentiation, and proliferation under pathological conditions including wound healing, tumorgenesis, and fibrogenesis in the adult. Recently we demonstrated the expression of two secreted FGFs, FGF16, and FGF18, in HUVEC and in rat aortic tissue. In the present report, we confirmed by RT-PCR analysis that FGF18 is wildly expressed in the cardiovascular tissue, while FGF16 showed a more restricted expression pattern. HUVEC clearly demonstrated chemotaxis towards FGF16 and FGF18. Both FGFs also enhanced cell migration in response to mechanical damage. However, recombinant FGF16 and FGF18 failed to induce endothelial cell proliferation or sprouting in a three-dimensional in vitro angiogenesis assay. Fgf18 expression was earlier reported in the liver, and we detected FGF18 expression in liver vascular and liver sinusoidal endothelial cells (LSECs), but not in hepatic parenchymal cells. Recombinant FGF18 stimulated DNA synthesis in primary hepatocytes, suggesting, that endothelial FGF18 might have a paracrine function in promoting growth of the parenchymal tissue. Interestingly, FGF2, which is mitogenic on endothelial cells and hepatocytes stimulates a sustained MAPK activation in both cell types, while FGF18 causes a short transient activation of the MAPK pathway in endothelial cells but a sustained activation in hepatocytes. Therefore, the difference in the time course of MAPK activation by the different FGFs appears to be the cause for the different cellular responses.
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PMID:Fibroblast growth factor 16 and 18 are expressed in human cardiovascular tissues and induce on endothelial cells migration but not proliferation. 1675 58


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