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)

FOXO proteins are transcriptional regulators that control cell cycle progression, DNA repair, defense against oxidative damage and apoptosis. These divergent functions of FOXO proteins are regulated by signal-induced, post-translational modifications. Phosphorylation of cytoplasmic FOXO at specific sites by JNK initiates translocation into the nucleus. Acetylation and deacetylation of nuclear FOXO affects the selection of transcriptional programs that are controlled by FOXO proteins. Activation of Akt by growth factors results in phosphorylation of nuclear FOXO at specific sites followed by additional phosphorylations mediated by other kinases. Akt-dependent phosphorylation reduces the DNA-binding activity of FOXO, interferes with binding to the co-activators p300/CBP, and inactivates the FOXO nuclear translocation signal. The Akt-phosphorylated FOXO is exported from the nucleus in a CRM1- and 14-3-3-dependent process. Cytoplasmic, Akt-phosphorylated FOXO interacts with the ubiquitin ligase Skp2 and is targeted for proteasomal degradation. The nuclear-cytoplasmic "FOXO shuttle" is driven by stress signals that result in nuclear import and FOXO transcriptional activity and growth signals that initiate nuclear export and proteasomal degradation of FOXO.
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PMID:Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. 1591 64

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

RARs (retinoic acid receptors) mediate the effect of their ligand RA (retinoic acid) on gene expression. We previously showed that RA inhibited cellular proliferation in part by decreasing expression of the mitogen activated protein kinase ERK1 (extracellular signal regulated kinase 1). However, the mechanism by which RA regulates ERK1 expression is largely uncharacterized. The present study characterizes coactivator-mediated regulation of RA target gene expression by analysing ERK1 promoter activation. CBP (CREB-binding protein) and PCAF (p300/CBP associated factor) are transcriptional coactivators that interact with nuclear hormone receptors such as RARs. CBP and PCAF differentially regulated ERK1 expression in stable clones. CBP clones expressed higher ERK1 protein levels, proliferated faster in culture and were resistant to RA-mediated growth inhibition. PCAF clones expressed lower levels of ERK1 protein and cells grew more slowly than controls. CBP and PCAF regulation of the ERK1 promoter was dependent on two Sp1 (specificity protein 1) sites located between -86 and -115 bp. Immunoprecipitation and yeast two-hybrid analysis revealed that PCAF interacted with Sp1 via CBP. A putative p53 binding site at -360 bp functioned as a major repressor of ERK1 promoter activity even in the absence of exogenous p53 expression. CBP and PCAF occupancy of the proximal ERK1 promoter was dramatically decreased by RA treatment. PCAF mediated inhibition of ERK1 expression was due to decreased stability of the kinase mRNA. We conclude that CBP and PCAF coactivators mediate ERK1 gene expression at both the transcriptional and post-transcriptional level.
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PMID:Regulation of ERK1 gene expression by coactivator proteins. 1605 Aug 10

Hypoxia-inducible factor 1 (HIF-1) plays a critical role in controlling oxygen delivery and metabolic adaptation to hypoxic conditions in hypoxic tumor cells. HIF-1 activation is initiated by several factors including mitogen-activated protein kinase (MAPK) superfamily. We have previously reported that mitogen-activated protein kinase phosphatase DUSP1 (MKP-1) was implicated in the negative regulation of HIF-1alpha subunit phosphorylation and HIF-1 activity. However, the molecular basis by which MKP-1 influences HIF-1 activity is not clarified. In this paper, we show that hypoxia transcriptionally induces MKP-1 expression in a time-dependent manner. Meanwhile, hypoxia also activates extracellular signal-regulated kinase (ERK) whose activity is enhanced or reduced by MKP-1 suppression or MKP-1 overexpression, respectively. We also show that suppression of MKP-1 expression facilitates the interaction between HIF-1alpha subunit and p300, a co-activator of HIF-1. Moreover, MKP-1 suppression leads to enhanced HIF-1 activity, which can be counteracted by PD98059, an ERK kinase inhibitor. Taken together, the results presented here suggest that hypoxia-induced MKP-1 protects overactivation of HIF-1 activation through inhibiting ERK kinase activity.
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PMID:Dual-specificity phosphatase DUSP1 protects overactivation of hypoxia-inducible factor 1 through inactivating ERK MAPK. 1608 Oct 65

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

TCR signaling leading to thymocyte apoptosis is mediated through the expression of the Nur77 family of orphan nuclear receptors. It has been shown that the Nur77 promoter is activated by at least two signaling pathways, one mediated by calcium and the other by protein kinase C (PKC). MEF2D has been known to regulate Nur77 expression in a calcium- dependent manner. The mechanism by which calcium regulates MEF2D is through dissociation of calcium-sensitive MEF2 corepressors (Cabin1/HDACs, HDAC4/5) and the association with calcineurin-activated transcription factor NF-AT and the coactivator p300. However, little is known about how PKC activates the Nur77 promoter. Herein, we report that PKCtheta targets AP-1 like response element in the Nur77 promoter where JunD constitutively binds. PKCtheta triggers mitogen-activated protein kinase-inediated phosphorylation of JunD, and increases transcriptional activity of JunD, cooperatively with p300. Menin is identified as the transcriptional corepressor for JunD via recruitment of mSin3-istone deacetylases. In fact, Menin represses PKCtheta/p300-mediated transcriptional activity of JunD in T cell. Its dynamic regulation of histone modifiers with JunD is responsible for PKCq-synergistic effect on Nur77 expression in T cell.
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PMID:Menin represses JunD transcriptional activity in protein kinase C theta-mediated Nur77 expression. 1626 71

Tumor necrosis factor-alpha (TNF-alpha) has been shown to induce the expression of adhesion molecules in airway resident cells and contribute to inflammatory responses. Here, the roles of mitogen-activated protein kinases (MAPKs) and NF-kappaB in TNF-alpha-induced expression of vascular cell adhesion molecule (VCAM)-1 were investigated in human tracheal smooth muscle cells (HTSMCs). TNF-alpha-enhanced expression of VCAM-1 protein and mRNA as well as phosphorylation of p42/p44 MAPK, p38, and JNK were significantly attenuated by inhibitors of MEK1/2 (U0126), p38 (SB202190), and JNK (SP600125). Transfection with dominant negative mutants of MEK1/2, ERK1, ERK2, p38, and JNK attenuated TNF-alpha-induced VCAM-1 expression. Furthermore, TNF-alpha-induced VCAM-1 expression was significantly blocked by a selective NF-kappaB inhibitor helenalin. TNF-alpha-stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaB-alpha was blocked by helenalin, but not by U0126, SB202190, or SP600125. VCAM-1 promoter activity was enhanced by TNF-alpha in HTSMCs transfected with VCAM-1-Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Most surprisingly, VCAM-1 expression was also significantly blocked by a selective inhibitor of p300, curcumin. NF-kappaB transcription factor and p300 were associated with the VCAM-1 promoter, which was dynamically linked to histone H3 acetylation stimulated by TNF-alpha, as determined by chromatin immunoprecipitation assay. Moreover, the resultant enhancement of VCAM-1 expression increased the adhesion of polymorphonuclear cells (PMNs) to monolayer of HTSMCs, which was blocked by helenalin, U0126, SB202190, or SP600125. These results suggest that in HTSMCs, activation of MAPK pathways, NF-kappaB, and p300 is essential for TNF-alpha-induced VCAM-1 expression.
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PMID:Transcriptional regulation of VCAM-1 expression by tumor necrosis factor-alpha in human tracheal smooth muscle cells: involvement of MAPKs, NF-kappaB, p300, and histone acetylation. 1628 71

NF-IL6beta regulates gene expression and plays function roles in many tissues. The EGF-regulated cyclooxygenase-2 (cox-2) expression is mediated through p38(MAPK) signaling pathway and positively correlates with NF-IL6beta expression in A431 cells. NF-IL6beta coordinated with c-Jun on cox-2 transcriptional activation by reporter and small interfering RNA assays. NF-IL6beta could directly bind to CCAAT/enhancer-binding protein (C/EBP) and cyclic AMP-response element (CRE) sites of the cox-2 promoter by in vitro-DNA binding assay. The C/EBP site was important for basal and, to a lesser extent, for EGF-regulated cox-2 transcription, while the CRE site was a more specific response to EGF inducibility of cox-2 gene. SUMO1 expression attenuated EGF- and NF-IL6beta-induced cox-2 promoter activities. NF-IL6beta was found to be sumoylated by in vivo- and in vitro-sumoylation assays, and the SUMO1-NF-IL6beta (suNF-IL6beta) lost its ability to interact with p300 in in vitro-binding assay. NF-IL6beta was also acetylated by p300, and acetylation of NF-IL6beta enhanced the cox-2 promoter activity stimulated by NF-IL6beta itself. In vivo-DNA binding assay demonstrated that EGF stimulated the recruitment of p300 and NF-IL6beta to the cox-2 promoter, yet promoted the dissociation of SUMO1-modificated proteins from the promoter. These results indicated that NF-IL6beta plays a pivotal role in the regulation of basal and EGF-induced cox-2 transcription.
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PMID:Functional role of NF-IL6beta and its sumoylation and acetylation modifications in promoter activation of cyclooxygenase 2 gene. 1639

Reactive oxygen species have been shown to play an important role in the regulation of distinct signaling cascades, many of which act upon the production of matrix metalloproteinases (MMP). Using a series of redox-engineered cell lines we have previously demonstrated that MMP-1 expression is sensitive to the alterations in the steady state production of H2O2 (Ranganathan, A. C., Nelson, K. K., Rodriguez, A. M., Kim, K. H., Tower, G. B., Rutter, J. L., Brinckerhoff, C. E., Epstein, C. J., Huang, T. T., Jeffrey, J. J., and Melendez, J. A. (2001) J. Biol. Chem. 276, 14264-14270). In the present study, we investigate the molecular mechanisms involved in the H2O2-mediated induction of MMP-1. Mutational analysis of an MMP-1 promoter indicates that both the single nucleotide polymorphism creating an Ets binding site at -1607 and a proximal AP-1 site at -1602 are required for maximal H2O2-dependent transcription. The redox-sensitive MMP-1 protein expression requires activation of both ERK1/2 and JNK pathways. Importantly, JNK signaling is largely responsible for the H2O2 sensitivity of the MMP-1 promoter, whereas ERK1/2 contributes to both its basal and H2O2 dependence. H2O2 control of Ets-1 expression was ERK1/2-dependent whereas that of c-Jun requires both ERK1/2 and JNK signaling. Chromatin immunoprecipitation assays indicate that binding of the histone acetyltransferase, p300, and the transcription factors Ets-1 and c-Jun to the MMP-1 promoter is redox sensitive. The redox sensitivity of MMP-1 expression is also associated with an increase in the abundance of oxidatively inactivated protein-tyrosine phosphatases. Targeted cytosolic or mitochondrial scavenging of H2O2 prevented all of the aforementioned signals. These studies provide substantial insight into the mechanisms underlying the redox-dependent control of MMP-1 and may lead to the development of novel targeted antioxidant-based inhibitory therapies for controlling MMP-1 expression during degenerative disease processes.
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PMID:Redox-dependent matrix metalloproteinase-1 expression is regulated by JNK through Ets and AP-1 promoter motifs. 1656 38


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