Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Necrotizing enterocolitis (NEC), a severe intestinal inflammation in neonates, occurs following bacterial colonization of the gut. LPS-induced production of inflammatory factors in immature enterocytes may be a factor in NEC. Previously, we described LPS-induced p38 MAPK-dependent expression of cyclooxygenase-2 (COX-2) in rat IEC-6 cells. In this study, we examine COX-2 expression in newborn rat intestinal epithelium and further characterize the mechanisms of COX-2 regulation in enterocytes. Induction of NEC by formula feeding/hypoxia increased phospho-p38 and COX-2 levels in the intestinal mucosa. Celecoxib, a selective COX-2 inhibitor, exacerbated the disease, suggesting a protective role for COX-2. COX-2 was induced in the intestinal epithelium by LPS in vivo and ex vivo. The latter response was attenuated by the p38 inhibitor SB202190, but not by inhibitors of ERK, JNK, or NF-kappaB. In IEC-6 enterocytes, COX-2 was induced by the expression of MAPK kinase 3 EE (MKK3EE), a constitutive activator of p38, but not of activators of ERK or JNK pathways. However, neither MKK3/6 nor MKK4, the known p38 upstream kinases, were activated by LPS. Dominant-negative MKK3 or MKK4 or SB202190 failed to prevent LPS-induced, p38-activating phosphorylation, ruling out important roles of these kinases or p38 autophosphorylation. LPS increased COX-2 and activating phosphorylation of p38 with similar dose-response. Blockade of LPS-induced expression of COX-2-luciferase reporter and destabilization of COX-2 message by SB202190 indicate that p38 regulates COX-2 at transcription and mRNA stability levels. Our data indicate that p38-mediated expression of COX-2 proceeds through a novel upstream pathway and support the role of the neonate's enterocytes as bacterial sensors.
 ...
PMID:Lipopolysaccharide induces cyclooxygenase-2 in intestinal epithelium via a noncanonical p38 MAPK pathway. 1636 53

The RET proto-oncogene is the major gene involved in the pathogenesis of Hirschsprung (HSCR), a complex genetic disease characterized by lack of ganglia along variable lengths of the gut. Here we present a survey of the different molecular mechanisms through which RET mutations lead to the disease development. Among these, loss of function, gain of function, apoptosis, aberrant splicing and decreased gene expression are exemplified and considered with respect to their pathogenetic impact. In particular, RET transcription regulation represents a new insight into the outline of HSCR susceptibility, and having reached important progress in the last few years, deserves to be reviewed. Notably, gene expression impairment seems to be at the basis of the association of HSCR disease with several RET polymorphisms, allowing us to define a predisposing haplotype spanning from the promoter to exon 2. Putative functional variants, in the promoter and in intron 1, and proposed as low penetrant predisposing alleles, are presented and discussed. Finally, based on the RET mutation effects thus summarized, we attempt to derive conclusions which may be useful for HSCR risk prediction and genetic counselling.
 ...
PMID:Molecular mechanisms of RET-induced Hirschsprung pathogenesis. 1644 84

The enteric nervous system (ENS) is composed of neurons and glial cells, organized as interconnected ganglia within the gut wall, which controls peristalsis of the gut wall and secretions from its glands. The Ret receptor tyrosine kinase is expressed throughout enteric neurogenesis and is required for normal ENS development; humans with mutations in the RET locus have Hirschsprung disease (HSCR, an absence of ganglia in the colon), and mice lacking Ret have total intestinal aganglionosis. The Ret mutant mouse provides a tool for identifying genes implicated in development of the ENS. By using RNA from WT and Ret mutant (aganglionic) gut tissue and DNA microarrays, we have conducted a differential screen for ENS-expressed genes and have identified hundreds of candidate ENS-expressed genes. Forty-seven genes were selected for further analysis, representing diverse functional classes. We show that all of the analyzed genes are expressed in the ENS and that the screen was sensitive enough to identify genes marking only subpopulations of ENS cells. Our screen, therefore, was reliable and sensitive and has identified many previously undescribed genes for studying ENS development. Moreover, two of the genes identified in our screen Arhgef3 and Ctnnal1, have human homologues that map to previously identified HSCR susceptibility loci, thus representing excellent candidates for HSCR genes. This comprehensive profile of ENS gene expression refines our understanding of ENS development and serves as a resource for future developmental, biochemical, and human genetic studies.
 ...
PMID:Expression profiling the developing mammalian enteric nervous system identifies marker and candidate Hirschsprung disease genes. 1663 97

Although proglucagon gene expression and the synthesis of proglucagon encoded peptide hormones could be activated by protein kinase A (PKA) activators such as forskolin/3-isobutyl-1-methylxanthine (IBMX) and cholera toxin, whether the activation is entirely attributed to PKA has not been previously examined. We found that forskolin/IBMX also activate ERK1/2 phosphorylation in intestinal and pancreatic proglucagon-producing cell lines. The MEK inhibitors PD98059 and U0126 were found to repress the expression of proglucagon promoter as well as endogenous proglucagon mRNA in two intestinal proglucagon-producing cell lines and to block the stimulatory effect of forskolin/IBMX on proglucagon mRNA expression. The repressive effect of the PKA-specific inhibitors H-89 and KT-5720, however, was either not observable or much less potent. Forskolin could activate ERK1/2 phosphorylation and proglucagon gene transcription on its own, whereas forskolin plus IBMX are required to effectively activate the PKA pathway in the proglucagon-producing cells. Exchange protein directly activated by cyclic AMP 2 (Epac2, or cAMP-binding guanine nucleotide exchange factor-2) was found to be expressed in gut and pancreatic proglucagon-producing cell lines, whereas the Epac-pathway-specific cAMP analog, 8-pMeOPT-2'O-Me-cAMP, effectively stimulated ERK1/2 phosphorylation as well as proglucagon mRNA expression. We therefore suggest that cAMP at least partially regulates proglucagon gene expression via the Epac-Ras/Rap-Raf-MEK-ERK signaling pathway.
 ...
PMID:Role of the exchange protein directly activated by cyclic adenosine 5'-monophosphate (Epac) pathway in regulating proglucagon gene expression in intestinal endocrine L cells. 1664 15

We studied differential global gene expression in four melanoma cell lines with three cell lines without homozygous deletion of the CDKN2A locus using HG-U133A microarrays with 22 277 transcripts. None of the cell lines carried mutations in the B-RAF and N-RAS genes. Data analysis using stringent criteria showed specific upregulation of 70 genes and downregulation of 86 genes in cell lines with homozygous deletion of the CDKN2A gene. A comparison with previous expression data showed overlapping of upregulation and downregulation of seven and 23 genes, respectively, in melanoma cell lines with homozygous deletion of the CDKN2A locus or mutations in the B-RAF and N-RAS genes. Microarray data for eight selected genes were validated with an extended number of cell lines using quantitative real-time polymerase chain reaction. The upregulated genes in cell lines with the deletion besides others included MAGE A2 [fold change 128, 95% confidence interval (CI) 82.8-172.2; t-test P=0.004], MAGE A6 (fold change 623, 95% CI 473.4-772.1; t-test P=0.001), MAGE A12 (fold change 90, 95% CI 65.1-115.5; t-test P=0.001) and dopachrome tautomerase (fold change 42, 95% CI 32.5-51.8; t-test P=0.001). Downregulated genes included interleukin 18 (fold change 489, 95% CI 146.4-831.2; t-test P=0.04), ID2 (fold change 3, 95% CI 2.2-4.9; t-test P=0.001), KLF4 (fold change 9, 95% CI 4.3-14.7; P=0.01) and CD24 antigen (fold change 1308, 95% CI 766.0-1850.8; t-test P=0.01). The upregulated genes common to cell lines with homozygous deletion of the CDKN2A gene and mutations in B-RAF and N-RAS gene included those that are involved in RAS/RAF/MEK/ERK pathways. Our results highlight effects of homozygous deletion of the CDKN2A locus on global gene expression.
 ...
PMID:Differences in global gene expression in melanoma cell lines with and without homozygous deletion of the CDKN2A locus genes. 1684 25

Hirschsprung disease (HSCR) is a congenital, heterogeneous disorder, characterized by the absence of intestinal ganglion cells. Recent advances show that the RET gene is a major locus involved in the pathogenesis of HSCR. The aim of this study was to analyse if the HSCR phenotype in the Polish population is associated with the presence of polymorphisms in exons 2, 3, 7, 11, 13, 14 and 15 of the RET gene. Molecular results were compared with clinical and long-term follow-up data in 70 Polish patients with HSCR (84.3% with a short segment and 15.7% with a long segment of aganglionic gut). Single-nucleotide polymorphisms were analysed by using the minisequencing SNaPshot multiplex method. The 135G>A polymorphism in RET exon 2 was overrepresented in HSCR patients, compared with a healthy control group. Moreover, the 135G>A variant was shown to be associated with the severe HSCR phenotype. Two other polymorphisms, 2071G>A in exon 11 and 2712C>G in exon 15, were underrepresented in the patients. The results confirm that these RET polymorphisms play a role in the aetiology of HSCR.
 ...
PMID:Single nucleotide polymorphisms in the RET gene and their correlations with Hirschsprung disease phenotype. 1687 7

Neurotensin (NT) is a brain-gut tridecapeptide that functions as a neurotransmitter/neuromodulator in the central nervous system (CNS) and as an endocrine agent in the periphery. NT has numerous physiologic effects on multiple organs. This review will focus on the effects of NT as a trophic factor for normal and neoplastic tissues. In this regard, NT may act as an endocrine agent or, in some instances, in a paracrine and/or autocrine fashion. These effects appear to be mediated predominantly through the G protein-coupled high-affinity NT receptor. However, some of the trophic effects may also be through the other two receptor subtypes, particularly the NT receptor type 3, which belongs to a recently identified family of sorting receptors. The signaling pathways mediating the effects of NT are multiple but most appear to activate the ERK signaling pathway, which then activates downstream transcription factors, ultimately leading to proliferation. NT may be a useful agent to enhance the growth of normal tissues such as the small bowel mucosa during periods of gut disuse or disease and, finally, the selective targeting of NT receptor subtypes on certain cancers may offer a novel strategy in the armamentarium of cancer chemotherapeutics.
 ...
PMID:Neurotensin and growth of normal and neoplastic tissues. 1690 38

The neurons and glia that comprise the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, are derived from vagal and sacral regions of the neural crest. In order to form the ENS, neural crest-derived precursors undergo a number of processes including survival, migration and proliferation, prior to differentiation into neuronal subtypes, some of which form functional connections with the gut smooth muscle. Investigation of the developmental processes that underlie ENS formation has progressed dramatically in recent years, in no small part due to the attention of scientists from a range of disciplines on the genesis of Hirschsprung's disease (aganglionic megacolon), the major congenital abnormality of the ENS. This review summarizes recent advances in the field of early ENS ontogeny and focuses on: (i) the spatiotemporal migratory pathways followed by vagal and sacral neural crest-derived ENS precursors, including recent in vivo imaging of migrating crest cells within the gut, (ii) the roles of the RET and EDNRB signalling pathways and how these pathways interact to control ENS development, and (iii) how perpendicular migrations of neural crest cells within the gut lead to the formation of the myenteric and submucosal plexi located between the smooth muscle layers of the gut wall.
 ...
PMID:Advances in ontogeny of the enteric nervous system. 1696 90

Complex diseases are common genetic disorders showing familial aggregation but no typical Mendelian inheritance. Hirschsprung disease (HSCR), a developmental disorder characterized by the absence of enteric neurons in distal segments of the gut, shows a complex pattern of inheritance, with the RET protooncogene acting as a major gene and additional susceptibility loci playing minor roles. In the last years, we have identified a "protective" RET haplotype, which is underrepresented in HSCR patients with respect to controls. Here, we demonstrate that the protective effect of this haplotype is due to a variant located in the 3' untranslated region (UTR) of the RET gene, which slows down the physiological mRNA decay of the gene transcripts. Such a functional effect of this common RET variant explains the under-representation of the whole haplotype and its role as a modifying factor in HSCR pathogenesis.
 ...
PMID:A common variant located in the 3'UTR of the RET gene is associated with protection from Hirschsprung disease. 1698 22

The RET receptor tyrosine kinase plays a critical role in the development of the enteric nervous system (ENS) and the kidney. Upon glial-cell-line-derived neurotrophic factor (GDNF) stimulation, RET can activate a variety of intracellular signals, including the Ras/mitogen-activated protein kinase, phosphatidylinositol 3-kinase (PI3K)/AKT, and RAC1/JUN NH(2)-terminal kinase (JNK) pathways. We recently demonstrated that the RAC1/JNK pathway is regulated by serine phosphorylation at the juxtamembrane region of RET in a cAMP-dependent manner. To determine the importance of cAMP-dependent modification of the RET signal in vivo, we generated mutant mice in which serine residue 697, a putative protein kinase A (PKA) phosphorylation site, was replaced with alanine (designated S697A mice). Homozygous S697A mutant mice lacked the ENS in the distal colon, resulting from a migration defect of enteric neural crest cells (ENCCs). In vitro organ culture showed an impaired chemoattractant response of the mutant ENCCs to GDNF. JNK activation by GDNF but not ERK, AKT and SRC activation was markedly reduced in neurons derived from the mutant mice. The JNK inhibitor SP600125 and the PKA inhibitor KT5720 suppressed migration of the ENCCs in cultured guts from wild-type mice to comparable degrees. Thus, these findings indicated that cAMP-dependent modification of RET function regulates the JNK signaling responsible for proper migration of the ENCCs in the developing gut.
 ...
PMID:Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. 1705 Jun 26


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