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)

Stable transformation of rat embryo fibroblast (REF) cells with E1A and cHa-ras oncogenes leads to downmodulation of c-fos gene transcription. This repression is provided in part by the association of Elk-1 transcription factor with histone deacetylases mediated through effects of Ras on MAP-kinase cascades. Here, we focus on the primary effects of E1A and Ras displayed in transient transfection assay on the transactivating capability of Elk-1, which is a key transcription factor of c-fos gene regulation. Our data show that E1A is able to suppress serum- and Ras-induced stimulation of Gal-luc reporter activity by a full-length Gal-Elk1-428 fusion protein as well as the expression of c-fos promoter-driven luciferase constructs (fos-luc). The repression can be relieved by trichostatin A, a histone deacetylase (HDAC) inhibitor, implying the involvement of HDACs and an inactive chromatin structure formed due to underacetylation of nucleosomal histones. Thus, upon transient transfection of E1A and Ras oncogenes in REF52 cells or their stable expression in E1A+cHa-ras cells, E1A contributes to the formation of inactive chromatin structure through association with p300/CBP histone acetyltransferases at c-fos promoters, whereas Ras mediates its effect through constitutive activation of the MAP/ERK kinase cascade, thereby promoting the recruitment of HDAC1 to the Elk-1 transcription factor. As a result, downregulation of c-fos gene transcription revealed in established E1A+Ras transformants is unlikely to be a consequence of cell transformation itself, but follows from primary effects of E1A and Ras on chromatin remodeling factors.
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PMID:Transient expression of E1A and Ras oncogenes causes downregulation of c-fos gene transcription in nontransformed REF52 cells. 1457 29

Reactive oxygen species (ROS), either directly or via the formation of lipid peroxidation products, such as 4-hydroxy-2-nonenal, acrolein and F2-isoprostanes, may play a role in enhancing inflammation through the activation and phosphorylation of stress kinases (JNK, ERK, p38) and redox-sensitive transcription factors such as NF-kappaB and AP-1. This increases the expression of genes regulating a battery of distinct pro-inflammatory mediators. Acetylation by histone acetyltransferase (HAT) of specific lysine residues on the N-terminal tail of core histones, results in uncoiling of the DNA and increased accessibility to transcription factor binding. In contrast, histone deacetylation by histone deacetylase (HDAC) represses gene transcription by promoting DNA winding thereby limiting access to transcription factors. Oxidative stress activates NF-kappaB resulting in expression of pro-inflammatory mediators through the activation of intrinsic HAT activity on co-activator molecules. In addition, oxidative stress also inhibits HDAC activity and in doing so enhances inflammatory gene expression which leads to a chronic inflammatory response. Oxidative stress can also increase complex formation between the co-activator CBP/p300 and the p65 subunit of NF-kappaB suggesting a further role of oxidative stress in chromatin remodeling. The antioxidant and/or anti-inflammatory effects of thiol molecules (glutathione, N-acetyl-L-cysteine and N-acystelyn), dietary polyphenols (curcumin-diferuloylmethane and resveratrol), the bronchodilator theophylline and glucocorticoids have all been shown to play a role in either controlling NF-kappaB activation or chromatin remodeling through modulation of HDAC activity and subsequently inflammatory gene expression in lung epithelial cells. Thus, oxidative stress regulates both signal transduction and chromatin remodeling which in turn impacts on pro-inflammatory responses in the lungs.
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PMID:Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. 1531 24

Human androgen receptor (AR) associates with coactivator or corepressor proteins that modulate its activation in the presence of ligand. Early studies on AR coactivators in carcinoma of the prostate were hampered because of lack of respective antibodies. Investigations at mRNA level revealed that most benign and malignant prostate cells express common coactivators. AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy. Increased expression of these coactivators is associated with enhanced activation of the AR by the adrenal androgen dehydroepiandrosterone. Similar association between AR coactivator expression and high prostate cancer grade and stage was reported for RAC-3 (SRC-3). The transcriptional integrator CBP was detected in clinical specimens representing organ-confined prostate cancer, lymph node metastases and tumour cell lines. Agonistic effect of the nonsteroidal antiandrogen hydroxyflutamide was strongly potentiated in prostate cells transfected with CBP cDNA. A functional homologue of CBP, p300, is implicated in ligand-independent AR activation by interleukin-6. The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines. It was proposed that the cofactor ARA70 is a specific enhancer of AR action. However, research from other laboratories has demonstrated interaction between ARA70 and other steroid receptors. Although in some cases dominant-negative coactivator mutants inhibited proliferation of prostate cancer cells in vitro, confirmation from in vivo tumour models is missing. In summary, several abnormalities in AR coactivator expression and function are associated with prostate cancer progression.
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PMID:Expression and function of androgen receptor coactivators in prostate cancer. 1566 89

The three related 160-kDa proteins, SRC-1, TIF-2 and RAC-3, were initially identified as factors interacting with nuclear receptors. They have also been reported to potentiate the activity of other transcription factors such as AP-1 or NF-kappaB. The aim of this work was to identify whether SRC-1 interferes with the TGF-beta/Smad signaling pathway, and if so, to identify its underlying mechanisms of action. Using transient cell transfection experiments performed in human dermal fibroblasts with the Smad3/4-specific (SBE)4-lux reporter construct, as well as the human PAI-1 promoter, we determined that SRC-1 enhances TGF-beta-induced, Smad-mediated, transcription. Likewise, SRC-1 overexpression potentiated TGF-beta-induced upregulation of PAI-1 steady-state mRNA levels. Using a mammalian two-hybrid system, we demonstrated that SRC-1 interacts with the transcriptional co-activators p300/CBP, but not with Smad3. Overexpression of the adenovirus E1A oncoprotein, an inhibitor of CBP/p300 activity, prevented the enhancing effect of SRC-1 on Smad3/4-mediated transcription, indicating that p300/CBP may be required for SRC-1 effect. Such hypothesis was validated, as expression of a mutant form of SRC-1 lacking the CBP/p300-binding site failed to upregulate Smad3/4-dependent transcription, while full-length SRC-1 potentiated p300.Smad3 interactions. These results identify SRC-1 as a novel Smad3/4 transcriptional partner, facilitating the functional link between Smad3 and p300/CBP.
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PMID:The steroid receptor co-activator-1 (SRC-1) potentiates TGF-beta/Smad signaling: role of p300/CBP. 1568 32

The potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) induces activator protein-1 (AP-1) transcription factors, early response genes involved in a diverse set of transcriptional regulatory processes, and protein kinase C (PKC) activity. This work was designed to explore the signal transduction pathways involved in TPA regulation of 5-aminolevulinate synthase (ALAS) gene expression, the mitochondrial matrix enzyme that catalyzes the first and rate-limiting step of heme biosynthesis. We have previously reported that TPA causes repression of ALAS gene, but the signaling pathways mediating this effect remain elusive. The present study investigates the role of different cascades often implicated in the propagation of phorbol ester signaling. To explore this, we combined the transient overexpression of regulatory proteins involved in these pathways and the use of small cell permeant inhibitors in human hepatoma HepG2 cells. In these experimental conditions, we analyzed TPA action upon endogenous ALAS mRNA levels, as well as the promoter activity of a fusion reporter construct, harboring the TPA-responsive region of ALAS gene driving chloramphenicol acetyl transferase gene expression. We demonstrated that the participation of alpha isoform of PKC, phosphatidylinositol 3-kinase (PI3K), extracellular-signal regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK) is crucial for the end point response. Remarkably, in this case, ERK activation is achieved in a Ras/Raf/MEK-independent manner. We also propose that p90RSK would be a convergent point between PI3K and ERK pathways. Furthermore, we elucidated the crosstalk among the components of the cascades taking part in TPA-mediated ALAS repression. Finally, by overexpression of a constitutively active p90RSK and the coactivator, cAMP-response element protein (CREB)-binding protein (CBP), we reinforced our previous model, that implies competition between AP-1 and CREB for CBP.
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PMID:Repression of 5-aminolevulinate synthase gene by the potent tumor promoter, TPA, involves multiple signal transduction pathways. 1579 41

Several options for the endocrine treatment of non-organ-confined prostate cancer are available. They include surgical or medical removal of androgenic hormones or administration of non-steroidal anti-androgens. However, tumour progression after a period of remission of the disease inevitably occurs in virtually all patients. The androgen receptor (AR) is, in various tumour models, implicated in the development of therapy resistance but molecular mechanisms that by-pass the receptor have also been described. Adaptation mechanisms relevant to tumour recurrence include up-regulation of AR mRNA and protein, overexpression of AR coactivators, increased activation of mutated receptors by steroids and anti-androgens, and ligand-independent activation. For research studies, sublines that respond to but do not depend on androgen for their proliferation were generated. Coactivators SRC-1, TIF-2, RAC3, p300, CBP, Tip60, and gelsolin are highly expressed in endocrine therapy-resistant prostate cancer. AR point mutations are increasingly detected in relapsed cancers and contribute to the failure of endocrine therapy in a subgroup of patients. Ligand-independent activation of the AR by HER-2/neu and interleukin-6 is associated with activation of the signalling pathway of mitogen-activated protein kinase. Increased activity of intracellular kinases may affect cellular events in both an AR-dependent and -independent manner. Mitogen-activated protein kinases are strongly phosphorylated in endocrine therapy-resistant prostate tumours. Similarly, activation of the AR by phosphorylated protein kinase B, Akt, has also been reported in prostate cancer. Activation of the Akt pathway contributes to increased survival of prostate tumour cells.
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PMID:Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours. 1594 99

In studies of gene regulation of keratin 16, we reported previously that simian virus 40 promoter factor 1 shows a functional cooperation with c-Jun and coactivators p300/CBP in driving the transcriptional regulation of epidermal growth factor (EGF)-induced keratin 16 gene expression. In the present study, we found that the stimulated expression of keratin 16 by EGF was mediated mainly through the mitogen-activated protein kinase kinase-extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway. Ser63 and Ser73 on the c-Jun NH(2)-terminal transactivation domain could be phosphorylated in cells treated with EGF; nevertheless, we found that the c-Jun COOH terminus played a pivotal role in EGF-induced expression of keratin 16. The activation of keratin 16 by EGF treatment could not be enhanced by the overexpression of myc-c-JunK3R, in which three putative acetylation lysine residues on the c-Jun COOH terminus were all mutated into arginines, suggesting that c-Jun acetylation on the COOH terminus might partially play a functional role in this system. In addition, by using a chromatin immunoprecipitation assay and a DNA affinity precipitation assay, EGF treatment up-regulated the p300 recruitment through ERK signaling to the promoter region in regulating keratin 16 transcriptional activity. Furthermore, the enhancement of acetyl-histone H3 to the keratin 16 chromatin promoter induced by EGF was also mediated via ERK activation. In conclusion, these results strongly suggest that both c-Jun induction and p300 recruitment to gene promoter, mediated through ERK activation, played an essential role in regulating keratin 16 gene expression by EGF. p300 mediated and regulated EGF-induced keratin 16 gene expression, at least in part, through multiple mechanisms, including a selective acetylation of c-Jun and histone H3.
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PMID:Activation of extracellular signal-regulated kinase signaling by epidermal growth factor mediates c-Jun activation and p300 recruitment in keratin 16 gene expression. 1621 53

An RTK-Ras-mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in vulval induction in Caenorhabditis elegans. We have previously carried out screens for suppressors of activated Ras to identify factors that play critical roles in the regulation of the pathway. ku258 was isolated as a semidominant allele that suppresses the Multivulva phenotype caused by activated let-60 ras. Our genetic and molecular analyses indicate that ku258 is a gain-of-function allele resulting from two point mutations in the C. elegans homolog of the transcriptional coactivator p300/CBP, cbp-1. Genetic data also suggest that cbp-1 may act downstream of the Ras signaling pathway, but not primarily downstream of the Wnt signaling pathway, to negatively regulate vulval cell fate specification. cbp-1 may function in concert with LIN-1, an Ets transcription factor family member that is one of the targets of MAPK. In vitro histone acetylation assays have revealed that together, the two point mutations cause a sevenfold increase in the histone acetyltransferase (HAT) activity of recombinant CBP-1. To our knowledge, this is the only such HAT activity mutation isolated in a CBP/p300 family protein, and this mutation may define a negative role of the HAT activity in antagonizing Ras function in a specific developmental event.
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PMID:A gain-of-function allele of cbp-1, the Caenorhabditis elegans ortholog of the mammalian CBP/p300 gene, causes an increase in histone acetyltransferase activity and antagonism of activated Ras. 1622 93

Growth regulation of the tandemly repeated ribosomal RNA (rRNA) genes in mammals can potentially occur by several distinct mechanisms. Only a fraction of the 200 or so rRNA genes appears to be activated in somatic cells, leaving open the possibility that enhanced transcription could result from gene activation events. Here we have determined the active rRNA gene count after growth stimulation with EGF, direct Raf activation and chromatin hyperacetylation and after inhibiting MAP-kinase signaling. Despite robust changes in rRNA transcription rates, we find no significant variation in active gene number in either mouse fibroblasts or human neuroepithelioma cells. Interestingly, the data also show that rRNA transcription enhancement induced by hyperacetylation is dependent on MEK/ERK signaling. Since ERK and the acetyltransferase CBP both bind the architectural factor UBF, this suggests a mechanism for targeting active CBP to the rRNA genes.
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PMID:Regulation of rRNA synthesis in human and mouse cells is not determined by changes in active gene count. 1658 37

Endocrine therapy for advanced prostate cancer is based on androgen ablation or blockade of the androgen receptor (AR). AR action in prostate cancer has been investigated in a number of cell lines, their derivatives, and transgenic animals. AR expression is heterogenous in prostate cancer in vivo; it could be detected in most primary tumors and their metastases. However, some cells lack the AR because of epigenetic changes in the gene promoter. AR expression increases after chronic androgen ablation in vitro. In several xenografts, AR upregulation is the most consistent change identified during progression towards therapy resistance. In contrast, the AR pathway may be by-passed during chronic treatment with a nonsteroidal anti-androgen. AR sensitivity in prostate cancer increases as a result of activation of the Ras/mitogen-activated protein kinase pathway. One of the major difficulties in endocrine therapy for prostate cancer is acquisition of agonistic properties of AR antagonists observed in the presence of mutated AR. Enhancement of AR function by associated coactivator proteins has been extensively investigated. Cofactors SRC-1, RAC3, p300/CBP, TIF-2, and Tip60 are upregulated in advanced prostate cancer. Most studies on ligand-independent activation of the AR are focused on Her-2/neu and interleukin-6 (IL-6). On the basis of studies that showed overexpression and activation of the AR in advanced prostate cancer, it was suggested that novel therapies that reduce AR expression will provide a benefit to patients. There is experimental evidence showing that prostate tumor growth in vitro and in vivo is inhibited following administration of chemopreventive drugs or antisense oligonucleotides that downregulate AR mRNA and protein expression.
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PMID:Androgen axis in prostate cancer. 1659 69


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