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

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of catecholamines. Expression of the tyrosine hydroxylase gene is regulated at the transcriptional level by extracellular signalling molecules, including epidermal growth factor (EGF), nerve growth factor (NGF) and glucocorticoids. We have analysed the stimulation of tyrosine hydroxylase gene transcription by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in noradrenergic locus coeruleus-like CATH.a cells and observed a striking enhancement of the transcriptional activation potential of the ternary complex factor Ets-like protein-1 (Elk-1), a key transcriptional regulator of serum response element-driven gene transcription. Likewise, TPA strongly up-regulated the biosynthesis of the transcription factor Egr-1 via distal serum response elements within the Egr-1 5'-flanking region. Subsequently, enhancement of the transcriptional activation potential of Egr-1 was observed. Overexpression of Egr-1 was sufficient to activate transcription of a tyrosine hydroxylase promoter/reporter gene, corroborating the view that the tyrosine hydroxylase gene is a target gene of Egr-1. Expression of dominant-negative mutants of Elk-1 or Egr-1 impaired TPA-induced stimulation of a tyrosine hydroxylase promoter/reporter gene transcription. In contrast, dominant-negative mutants of the transcription factors activating transcription factor (ATF)-2, ATF4, cAMP response element-binding protein, c-Jun and CCAAT/enhancer binding protein (C/EBP) did not change TPA-induced tyrosine hydroxylase promoter activity, indicating that these proteins are not part of the TPA-mediated signalling cascade directed towards the tyrosine hydroxylase gene.
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PMID:Up-regulation of tyrosine hydroxylase gene transcription by tetradecanoylphorbol acetate is mediated by the transcription factors Ets-like protein-1 (Elk-1) and Egr-1. 1651 41

C/EBPbeta is known to be important for monocytic differentiation and macrophage function. Here, we found that expression of all three C/EBPbeta isoforms induced in HL60 cells by 1,25-dihydroxyvitamin D3 (1,25D) was upregulated in a sustained manner that correlates with the appearance of monocytic phenotype and with the G1 phase cell cycle arrest. In 1,25D-resistant HL60-40AF cells, isoforms beta-1 and beta-3 were expressed at levels comparable to 1,25D-sensitive HL60-G cells, but isoform beta-2 was difficult to detect. Treatment of sensitive HL60 cells with 1,25D resulted in predominantly nuclear localization of C/EBP isoforms beta-2 and beta-3, while a large proportion of C/EBPbeta-1 remained in the cytoplasm. Attenuation of the MEK-ERK MAPK pathway by the inhibitor PD98059 markedly reduced the expression, 1,25D-induced phosphorylation and nuclear localization of C/EBPbeta-2 and C/EBPbeta-3. Interestingly, only the lower molecular mass isoforms of C/EBPbeta phosphorylated on Thr235 were found in the nuclei, while C/EBPbeta-1 was constitutively phosphorylated and was detected principally in the cytoplasmic fraction. Although the role of C/EBPbeta isoforms in 1,25D-induced differentiation is complex, our results taken together strongly suggest that the phosphorylation of C/EBPbeta isoforms on Thr235 takes place mainly via the MEK-ERK pathway and that C/EBPbeta-2 is the principal transcription factor in this cell system.
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PMID:Regulation of C/EBPbeta isoforms by MAPK pathways in HL60 cells induced to differentiate by 1,25-dihydroxyvitamin D3. 1662 84

Ependymomas are primary tumors of the central nervous system that typically originate from the walls of the cerebral ventricles or from the spinal canal. The pathogenesis of these tumors is poorly understood, and prognostic assessment based on histologic features and clinical parameters is difficult. The aim of this study was to investigate the molecular heterogeneity of ependymomas. We used cDNA microarrays and RT-PCR to examine gene expression in 47 ependymomas. We present results for five comparisons: (1) tumors from children and adults with poor versus favorable outcome, (2) tumors from children with poor versus favorable outcome, (3) tumors with high versus low proliferation indices, (4) subependymomas versus myxopapillary ependymomas, and (5) spinal versus intracranial ependymomas. For patients with an overall survival >10 years after diagnosis, we identified 27 genes associated with favorable prognosis. In contrast, overexpression of BNIP3, MRC1, EPHB3, GLIS3, CDK4, COL4A2, EBP, NRCAM, and CCNA1 genes in tumors with high proliferation indices was associated with a poor outcome. Thirty genes, including ETV6, YWHAE, TOP2A, TLR2, IRAK1, TIA1, and UFD1L were found to be highly expressed in subependymomas but not myxopapillary ependymomas. Also, 30 genes were differentially expressed in spinal versus intracranial ependymomas. There was no relationship between expression profiles and tumor grade, patient age, and patient gender. Our results provide insight into specific molecular events underlying ependymoma tumorigenesis and may contribute to more accurate diagnosis and prediction of clinical outcome.
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PMID:Ependymoma gene expression profiles associated with histological subtype, proliferation, and patient survival. 1726 49

Matrix metalloproteinases (MMPs) degrade collagen and mediate tissue remodeling. The novel cytokine IL-17 is expressed during various inflammatory conditions and modulates MMP expression. We investigated the effect of IL-17 on MMP-1 expression in primary human cardiac fibroblasts (HCF) and delineated the signaling pathways involved. HCF were treated with recombinant human IL-17. MMP-1 expression was analyzed by Northern blotting, RT-quantitative PCR, Western blotting, and ELISA; transcriptional induction and transcription factor binding by EMSA, ELISA, and reporter assay; and p38 MAPK and ERK1/2 activation by protein kinase assays and Western blotting. Signal transduction pathways were investigated using pharmacological inhibitors, small interfering RNA (siRNA), and adenoviral dominant-negative expression vectors. IL-17 stimulated MMP-1 gene transcription, net mRNA levels, protein, and promoter-reporter activity in HCF. This response was blocked by IL-17 receptor-Fc chimera and IL-17 receptor antibodies, but not by IL-6, TNF-alpha, or IL-1beta antibodies. IL-17-stimulated type I collagenase activity was inhibited by the MMP inhibitor GM-6001 and by siRNA-mediated MMP-1 knockdown. IL-17 stimulated activator protein-1 [AP-1 (c-Fos, c-Jun, and Fra-1)], NF-kappaB (p50 and p65), and CCAAT enhancer-binding protein (C/EBP)-beta DNA binding and reporter gene activities, effects attenuated by antisense oligonucleotides, siRNA-mediated knockdown, or expression of dominant-negative signaling proteins. Inhibition of AP-1, NF-kappaB, or C/EBP activation attenuated IL-17-stimulated MMP-1 expression. IL-17 induced p38 MAPK and ERK1/2 activation, and inhibition by SB-203580 and PD-98059 blunted IL-17-mediated transcription factor activation and MMP-1 expression. Our data indicate that IL-17 induces MMP-1 in human cardiac fibroblasts directly via p38 MAPK- and ERK-dependent AP-1, NF-kappaB, and C/EBP-beta activation and suggest that IL-17 may play a critical role in myocardial remodeling.
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PMID:IL-17 stimulates MMP-1 expression in primary human cardiac fibroblasts via p38 MAPK- and ERK1/2-dependent C/EBP-beta , NF-kappaB, and AP-1 activation. 1792 24

Proline-rich tyrosine kinase2 (Pyk2) is a cytoplasmic tyrosine kinase related to focal adhesion kinase. Pyk2 expression has been known to be restricted to neuronal and hematopoietic cells and Pyk2 tyrosine phosphorylation and its kinase activity is important for the function of monocytes/macrophages. In NB4 acute promyelocytic leukemia cells, the expression of Pyk2 was increased in parallel with differentiation, and inhibited by PD98059, indicating Pyk2 expression is regulated through MAPK/ERK pathway. Dominant-negative kinase-deficient mutant of Pyk2 reduced the differentiation of NB4 cells in response to phorbol 12-mystate 13-acetate. Transcription factor CCAAT enhancer-binding protein (C/EBP) beta was required to induce Pyk2 expression in promoter analysis. These results suggest that Pyk2 is induced and involved in monocyte differentiation and C/EBPbeta is a critical regulator of the Pyk2 expression.
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PMID:Induction of proline-rich tyrosine kinase2 (Pyk2) through C/EBPbeta is involved in PMA-induced monocyte differentiation. 1819 30

Transcription factor CCAAT/enhancer-binding protein (C/EBP)-beta is crucial for regulating transcription of genes involved in a number of diverse cellular processes, including those involved in some cytokine-induced responses. However, the mechanisms that contribute to its diverse transcriptional activity are not yet fully understood. To gain an understanding into its mechanisms of action, we took a proteomic approach and identified cellular proteins that associate with C/EBP-beta in an interferon (IFN)-gamma-dependent manner. Transcriptional mediator (Mediator) is a multisubunit protein complex that regulates signal-induced cellular gene transcription from enhancer-bound transcription factor(s). Here, we report that the Med1 subunit of the Mediator as a C/EBP-beta-interacting protein. Using gene knock-out cells and mutational and RNA interference approaches, we show that Med1 is critical for IFN-induced expression of certain genes. Med1 associates with C/EBP-beta through a domain located between amino acids 125 and 155 of its N terminus. We also show that the MAPK, ERK1/2, and an ERK phosphorylation site within regulatory domain 2, more specifically the Thr(189) residue, of C/EBP-beta are essential for it to bind to Med1. Last, an ERK-regulated site in Med1 protein is also essential for up-regulating IFN-induced transcription although not critical for binding to C/EBP-beta.
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PMID:The Med1 subunit of transcriptional mediator plays a central role in regulating CCAAT/enhancer-binding protein-beta-driven transcription in response to interferon-gamma. 1833 25

Certain flavonoids have been shown to have specific effects on biochemical and metabolic functions of adipocytes. In this study, we investigated the effects of combinations of resveratrol and quercetin on adipogenesis and apoptosis in 3T3-L1 cells. In maturing preadipocytes resveratrol and quercetin at 25 microM individually suppressed intracellular lipid accumulation by 9.4+/-3.9% (p<0.01) and 15.9+/-2.5%, respectively, (p<0.001). The combination of resveratrol and quercetin at the same dose, however, decreased lipid accumulation by 68.6+/-0.7% (p<0.001). In addition, combinations of resveratrol and quercetin at 25 microM significantly decreased the expression of peroxisome proliferators-activated receptor gamma (PPAR gamma) and CCAAT/enhancer-binding protein (C/EBP)alpha, both of which act as key transcription factors. In mature adipocytes resveratrol and quercetin at 100 microM individually decreased viability by 18.1+/-0.6% (p<0.001) and 15.8+/-1% (p<0.001) and increased apoptosis (100 microM) by 120.5+/-8.3% (p<0.001) and 85.3+/-10% (p<0.001) at 48 h, respectively. Combinations of resveratrol and quercetin further decreased viability (73.5+/-0.9%, p<0.001) and increased apoptosis (310.3+/-9.6%, p<0.001) more than single compounds alone. The combination of resveratrol and quercetin at 100 muM increased release of cytochrome c from mitochondria to cytosol and decreased ERK 1/2 phosphorylation. Taken together, our data indicate that combinations of resveratrol and quercetin can exert potential anti-obesity effects by inhibiting differentiation of preadipocytes and inducing apoptosis of mature adipocytes.
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PMID:Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin. 1843 93

We recently found that induction of the anti-inflammatory SOCS-3 gene by cyclic AMP occurs through novel cyclic AMP-dependent protein kinase-independent mechanisms involving activation of CCAAT/enhancer-binding protein (C/EBP) transcription factors, notably C/EBPbeta, by the cyclic AMP GEF EPAC1 and the Rap1 GTPase. In this study we show that down-regulation of phospholipase (PL) Cepsilon with small interfering RNA or blockade of PLC activity with chemical inhibitors ablates exchange protein directly activated by cyclic AMP (EPAC)-dependent induction of SOCS-3 in COS1 cells. Consistent with this, stimulation of cells with 1-oleoyl-2-acetyl-sn-glycerol and phorbol 12-myristate 13-acetate, both cell-permeable analogues of the PLC product diacylglycerol, are sufficient to induce SOCS-3 expression in a Ca2+-dependent manner. Moreover, the diacylglycerol- and Ca2+-dependent protein kinase C (PKC) isoform PKCalpha becomes activated following cyclic AMP elevation or EPAC stimulation. Conversely, down-regulation of PKC activity with chemical inhibitors or small interfering RNA-mediated depletion of PKCalpha or -delta blocks EPAC-dependent SOCS-3 induction. Using the MEK inhibitor U0126, we found that activation of ERK MAPKs is essential for SOCS-3 induction by either cyclic AMP or PKC. C/EBPbeta is known to be phosphorylated and activated by ERK. Accordingly, we found ERK activation to be essential for cyclic AMP-dependent C/EBP activation and C/EBPbeta-dependent SOCS-3 induction by cyclic AMP and PKC. Moreover, overexpression of a mutant form of C/EBPbeta (T235A), which lacks the ERK phosphorylation site, blocks SOCS-3 induction by cyclic AMP and PKC in a dominant-negative manner. Together, these results indicate that EPAC mediates novel regulatory cross-talk between the cyclic AMP and PKC signaling pathways leading to ERK- and C/EBPbeta-dependent induction of the SOCS-3 gene.
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PMID:Activation of protein kinase Calpha by EPAC1 is required for the ERK- and CCAAT/enhancer-binding protein beta-dependent induction of the SOCS-3 gene by cyclic AMP in COS1 cells. 1942 9

WNT5A is a cancer-associated gene involved in invasion and metastasis of melanoma, breast cancer, pancreatic cancer, and gastric cancer. WNT5A transduces signals through Frizzled, ROR1, ROR2 or RYK receptors to beta-catenin-TCF/LEF, DVL-RhoA-ROCK, DVL-RhoB-Rab4, DVL-Rac-JNK, DVL-aPKC, Calcineurin-NFAT, MAP3K7-NLK, MAP3K7-NF-kappaB, and DAG-PKC signaling cascades in a context-dependent manner. SNAI1 (Snail), CD44, G3BP2, and YAP1 are WNT5A target genes. We and other groups previously reported that IL6- or LIF-induced signaling through JAK-STAT3 signaling cascade is involved in WNT5A upregulation (STAT3-WNT5A signaling loop). Here, refined integrative genomic analyses of WNT5A were carried out to elucidate other mechanisms of WNT5A transcription. The WNT5A gene was found to encode two isoforms by using alternative first exons 1A and 1B. Quadruple Smad-binding elements (SBEs), single Sp1-binding site (GC-box), PPARgamma-binding site, C/EBP-binding site and bHLH-binding site within the promoter A region, 5'-adjacent to exon 1A, were conserved in human WNT5A, chimpanzee WNT5A, mouse Wnt5a, and rat Wnt5a. NF-kappaB-binding site, CUX1-binding site, double SBEs and double GC-boxes within the promoter B region, 5'-adjacent to exon 1B, were conserved in mammalian WNT5A orthologs. Quadruple FOX-binding sites and double SBEs within ultra-conserved intron 1 were also conserved in mammalian WNT5A orthologs. Conserved NF-kappaB-binding site within the WNT5A promoter B region elucidated the mechanisms that TNFalpha and toll-like receptor (TLR) signals upregulate WNT5A via MAP3K7. Quadruple FOX-binding sites rather than GLI-binding site revealed that Hedgehog signals induce WNT5A upregulation indirectly via FOX family members, such as FOXA2, FOXC2, FOXE1, FOXF1 and FOXL1. TGFbeta signals were found to upregulate WNT5A expression directly through the Smad complex, and also indirectly through Smad-induced CUX1 and MAP3K7-mediated NF-kappaB. Together these facts indicate that WNT5A is transcribed based on multiple mechanisms, such as NF-kappaB, Hedgehog, TGFbeta, and Notch signaling cascades.
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PMID:Transcriptional mechanisms of WNT5A based on NF-kappaB, Hedgehog, TGFbeta, and Notch signaling cascades. 1942 2

Preadipocyte factor-1 [Pref-1; also called Dlk1 (Delta-like protein 1)] is made as an epidermal growth factor-repeat containing transmembrane protein that produces a biologically active soluble form by TNF-alpha-converting enzyme (TACE)-mediated cleavage. Soluble Pref-1 activates the MAPK kinase/ERK pathway. In adipose tissue, Pref-1 is specifically expressed in preadipocytes but not in adipocytes and thus is used as a preadipocyte marker. Inhibition of adipogenesis by Pref-1 has been well established in vitro as well as in vivo by ablation and overexpression of Pref-1. SRY (sex determining region Y)-box 9 (Sox9), a transcription factor expressed in preadipocytes to suppress CCAAT enhancer binding protein beta and (C/EBP) delta expression, is required to be down-regulated before adipocyte differentiation can proceed. By activating MAPK kinase/ERK, Pref-1 prevents down-regulation of Sox9, resulting in inhibition of adipogenesis. Furthermore, by inducing Sox9, Pref-1 promotes chondrogenic induction of mesenchymal cells but prevents chondrocyte maturation as well as osteoblast differentiation. Thus, Pref-1 directs multipotent mesenchymal cells toward the chondrogenic lineage but inhibits differentiation into adipocytes as well as osteoblasts and chondrocytes. Pref-1, encoded by an imprinted gene, has also been detected in progenitor cells in various tissues during regeneration and therefore may have a more general role in maintaining cells in an undifferentiated state.
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PMID:Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate. 1954 43


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