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)

Molecular mapping techniques have defined the region of gene loss in two patients with the 5q- syndrome and uncharacteristically small 5q deletions (5q31-q33). The allelic loss of 10 genes localized to 5q23-qter (centromere-CSF2-EGR1-FGFA-GRL-ADRB2-CS F1R-SPARC-GLUH1-NKSF1-FLT4-telomere) was investigated in peripheral blood cell fractions. Gene dosage experiments demonstrated that CSF2, EGR1, NKSF1, and FLT4 were retained on the 5q- chromosome in both patients and that FGFA was retained in one patient, thus placing these genes outside the critical region. GRL, ADRB2, CSF1R, SPARC, and GLUH1 were shown to be deleted in both patients. The proximal breakpoint is localized between EGR1 and FGFA in one patient and between FGFA and ADRB2 in the other, and the distal breakpoint is localized between GLUH1 and NKSF1 in both patients. Pulsed-field gel electrophoresis was used to map the 5q deletion breakpoints, and breakpoint-specific fragments were detected with FGFA in the granulocyte but not the lymphocyte fraction of one patient. This study has established the critical region of gene loss of the 5q- chromosome in the 5q- syndrome, giving the location for a putative tumor-suppressor gene in the 5.6-Mb region between FGFA and NKSF1.
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PMID:Molecular mapping of uncharacteristically small 5q deletions in two patients with the 5q- syndrome: delineation of the critical region on 5q and identification of a 5q- breakpoint. 818 84

The q23-q33 region of human chromosome 5 encodes a large number of growth factors, growth factor receptors, and hormone/neurotransmitter receptors. This is also the general region into which several disease genes have been mapped, including diastrophic dysplasia, Treacher Collins syndrome, hereditary startle disease, the myeloid disorders that are associated with the 5q-syndrome, autosomal-dominant forms of hereditary deafness, and limb girdle muscular dystrophy. We have developed a framework physical map of this region using cosmid clones isolated from the Los Alamos arrayed chromosome 5-specific library. Entry points into this library included 14 probes to genes within this interval and one anonymous polymorphic marker locus. A physical map has been constructed using fluorescence in situ hybridization of these cosmids on metaphase and interphase chromosomes, and this is in good agreement with the radiation hybrid map of the region. The derived order of loci across the region is cen-IL4-IL5-IRF1-IL3-IL9-EGR1-CD1 4-FGFA-GRL-D5S207-ADRB2-SPARC-RPS14+ ++-CSF1R- ADRA1, and the total distance spanned by these loci is approximately 15 Mb. The framework map, genomic clones, and contig expansion within 5q23-q33 should provide valuable resources for the eventual isolation of the clinically relevant loci that reside in this region.
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PMID:A physical map of 15 loci on human chromosome 5q23-q33 by two-color fluorescence in situ hybridization. 832 47

Proliferation, differentiation, and apoptosis are tightly regulated during hematopoiesis, allowing amplification along specific lineages while preventing excessive proliferation of immature cells. The MCL1 member of the BCL2 family is up-regulated during the induction of monocytic differentiation (approximately 10-fold with 12-O-tetradecanoylphorbol 13-acetate (TPA)). MCL1 has effects similar to those of BCL2, up-regulation promoting viability, but differs from BCL2 in its rapid inducibility and its pattern of expression. Nuclear factors that regulate MCL1 transcription have now been identified, extending the previous demonstration of signal transduction through mitogen-activated protein kinase. A 162-base pair segment of the human MCL1 5'-flank was found to direct luciferase reporter activity, allowing approximately 10-fold induction with TPA that was suppressible upon inhibition of the extracellular signal-regulated kinase (ERK) pathway. Serum response factor (SRF), Elk-1, and Sp1 bound to cognate sites within this segment, SRF and Elk-1 acting coordinately to affect both basal activity and TPA inducibility, whereas Sp1 affected basal activity only. Thus, the mechanism of the TPA-induced increase in MCL1 expression seen in myelomonocytic cells at early stages of differentiation involves signal transduction through ERKs and transcriptional activation through SRF/Elk-1. This finding provides a parallel to early response genes (e.g. c-FOS and EGR1) that affect maturation commitment in these cells and therefore suggests a means through which enhancement of cell viability may be linked to the induction of differentiation.
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PMID:Regulation of MCL1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation. 988 May 63

Metastasis is the leading cause of treatment failure in medulloblastoma. Understanding the genetic regulation of metastasis may aid in the development of novel treatments. We therefore performed in silico analysis of the mRNA expression of 83 medulloblastomas compiled from two independent microarray studies by focusing on 135 genes most frequently linked to metastasis in other tumors. We then asked whether expression of these genes correlated with metastasis in the medulloblastoma array data sets. We found the platelet-derived growth factor receptor alpha, early growth response protein 1 and insulin-like growth factor 2 genes as well as several genes associated with MYCC and ERBB2 overexpressed by at least 2-fold in metastatic tumors in both array data sets. We conclude that these genes may interact to promote prometastatic signaling in medulloblastoma.
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PMID:The use of gene expression analysis to gain insights into signaling mechanisms of metastatic medulloblastoma. 1284 96

DeltaNp73alpha is an isoform of the p53 homologue p73 that lacks an amino-terminal transactivation domain and antagonizes the induction of gene expression by p53. Here, we examined whether DeltaNp73alpha might also modulate cellular transcription in the absence of p53. The expression of DeltaNp73alpha in the p53-/- cell line H1299 reduced the mRNA levels of p21/CDKN1A, but did not affect other p53-responsive genes. Correspondingly, the p21/CDKN1A promoter was downregulated by DeltaNp73alpha in reporter assays, whereas other p53-responsive promoters were not inhibited. To identify additional genes that respond to DeltaNp73alpha in the absence of p53, microarrays carrying 4600 cDNA clones were hybridized. The expression of 30 genes was found to be altered more than threefold by overexpressed DeltaNp73alpha. For instance, DeltaNp73alpha increased the expression of EGR1 and CDC6, whereas it decreased the mRNA levels of c-MYC, cyclin A2/CCNA2, NF-kappaB1, ODC1, and RET finger protein/RFP. Semiquantitative reverse transcription-PCR confirmed these results and further revealed that the influence of DeltaNp73alpha on the regulation of these genes differs from other p73 isoforms and p53. We conclude that the impact of DeltaNp73alpha on gene expression is not limited to p53-responsive genes. Rather, DeltaNp73alpha can regulate the expression of a variety of genes independently of p53.
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PMID:DeltaNp73 can modulate the expression of various genes in a p53-independent fashion. 1461 48

To better understand the molecular basis of chronic obstructive pulmonary disease (COPD), we used serial analysis of gene expression (SAGE) and microarray analysis to compare the gene expression patterns of lung tissues from COPD and control smokers. A total of 59,343 tags corresponding to 26,502 transcripts were sequenced in SAGE analyses. A total of 327 genes were differentially expressed (1.5-fold up- or down-regulated). Microarray analysis using the same RNA source detected 261 transcripts that were differentially expressed to a significant degree between GOLD-2 and GOLD-0 smokers. We confirmed the altered expression of a select number of genes by using real-time quantitative RT-PCR. These genes encode for transcription factors (EGR1 and FOS), growth factors or related proteins (CTGF, CYR61, CX3CL1, TGFB1, and PDGFRA), and extracellular matrix protein (COL1A1). Immunofluorescence studies on the same lung specimens localized the expression of Egr-1, CTGF, and Cyr61 to alveolar epithelial cells, airway epithelial cells, and stromal and inflammatory cells of GOLD-2 smokers. Cigarette smoke extract induced Egr-1 protein expression and increased Egr-1 DNA-binding activity in human lung fibroblast cells. Cytomix (tumor necrosis factor alpha, IL-1beta, and IFN-gamma) treatment showed that the activity of matrix metalloproteinase-2 (MMP-2) was increased in lung fibroblasts from EGR1 control (+/+) mice but not detected in that of EGR1 null (-/-) mice, whereas MMP-9 was regulated by EGR1 in a reverse manner. Our study represents the first comprehensive analysis of gene expression on GOLD-2 versus GOLD-0 smokers and reveals previously unreported candidate genes that may serve as potential molecular targets in COPD.
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PMID:Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. 1546 29

Recent interest in the health consequences of ricin as a weapon of terrorism has led us to investigate the effects of ricin on cells in vitro and in mice. Our previous studies showed that depurination of the 28S rRNA by ricin results in the inhibition of translation and the coordinate activation of the stress-activated protein kinases JNK and p38 MAPK. In RAW 264.7 macrophages, ricin induced the activation of ERK, JNK, and p38 MAPK, the accumulation of mRNA encoding tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, the transcription factors c-Fos, c-Jun, and EGR1, and the appearance of TNF-alpha protein in the culture medium. Using specific inhibitors of MAPKs, we demonstrated the nonredundant roles of the individual MAPKs in mediating proinflammatory gene activation in response to ricin. Similarly, the intravenous administration of ricin to mice led to the activation of ERK, JNK, and p38 MAPK in the kidneys, and increases in plasma-borne TNF-alpha, IL-1beta, and IL-6. Ricin-injected mice developed the hallmarks of hemolytic uremic syndrome, including thrombotic microangiopathy, hemolytic anemia, thrombocytopenia, and acute renal failure. Microarray analyses demonstrated a massive proinflammatory transcriptional response in the kidneys, coincidental with the symptoms of hemolytic uremic syndrome. Therapeutic management of the inflammatory response may affect the outcome of intoxication by ricin.
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PMID:Administration of ricin induces a severe inflammatory response via nonredundant stimulation of ERK, JNK, and P38 MAPK and provides a mouse model of hemolytic uremic syndrome. 1563 24

Neuroendocrine (NE) cells are found in prostate tumors, and their incidence is considered a promising prognostic indicator for the development of androgen-independent disease. NE cells are derived from non-NE prostate cancer cells and secrete factors that can act in a paracrine manner to stimulate the survival, growth, motility, and metastatic potential of prostatic carcinoma cells. Factors such as IL-6, epinephrine, and forskolin induce NE differentiation in prostate cancer cells; the mechanisms involve increases in intracellular cAMP, protein kinase A (PKA) activation and reduced intracellular calcium levels. Transcription factors implicated in the acquisition of NE characteristics by prostate cancer cells include STAT3, CREB, EGR1, c-fos, and NF-kappaB. Expression of Chromogranin A, neuron-specific enolase, bcl-2, and the androgen receptor are modulated during NE differentiation and serve as molecular markers for NE cells. Most importantly, NE cells secrete neuropeptides, such as bombesin, neurotensin, PTHrP, serotonin, and calcitonin, which trigger growth and survival responses in androgen-independent prostate cancer cells. Prostate cancer cell receptors that play a role in these processes include the gastrin-releasing peptide (GRP) receptor, neurotensin receptors, and the epidermal growth-factor receptor (EGFR). Signal-transduction molecules activated by these neuropeptides include Src, focal adhesion kinase (FAK), ERK, and PI3K/Akt, with subsequent activation of Elk-1, NF-kappaB, and c-myc transcription factors. A multitude of genes are then expressed by prostate cancer cells, which are involved in proliferation, anti-apoptosis, migration, metastasis, and angiogenesis. Targeting of these pathways at multiple levels can be exploited to inhibit the process by which NE cells contribute to the progression of androgen-independent, treatment-refractory prostate cancer.
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PMID:Neuroendocrine cells in prostate cancer. 1566 58

Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis. Consistent heterogeneity in chromosome number was found, and most cell lines showed a near-triploid chromosome complement. Several cell lines showed deletions of the TP53 (alias p53), CDKN2A (alias p16), and VHL genes. Multiplex fluorescence in situ hybridization (M-FISH) analysis revealed chromosome 3 translocated to several other partners chromosomes, as well as breakage events commonly affecting chromosomes 1, 5, 8, 10, and 17. The most common abnormality detected with comparative genomic hybridization (CGH) was deletions of chromosome 3p, with loss of the RASSF1, FHIT, and p44S10 loci frequently involved. CGH gain of 5q showed overrepresentation of the EGR1 and CSF1R genes. Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the EGFR, TIF1, and RFC2 genes. Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of CDK4 and SAS loci. M-FISH revealed several other recurrent translocations, and CGH findings included loss of 9p, 14q, and 18q and gain of 8q, 12, and 20. Further genomic microarray changes included loss of MTAP, IGH@, HTR1B, and SMAD4 (previously MADH4) and gains of MYC and TOP1. An excellent correlation was observed between the genomic array and FISH data, demonstrating that this technique is effective and accurate. The aberrations detected here may reflect important pathways in renal cancer pathogenesis.
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PMID:A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma. 1586 Mar 50

Germ cell tumors (GCTs) of the testis are the predominant cancer among young men. We analyzed gene expression profiles of 50 GCTs of various subtypes, and we compared them with 443 other common malignant tumors of epithelial, mesenchymal, and lymphoid origins. Significant differences in gene expression were found among major histological subtypes of GCTs, and between them and other malignancies. We identified 511 genes, belonging to several critical functional groups such as cell cycle progression, cell proliferation, and apoptosis, to be significantly differentially expressed in GCTs compared with other tumor types. Sixty-five genes were sufficient for the construction of a GCT class predictor of high predictive accuracy (100% training set, 96% test set), which might be useful in the diagnosis of tumors of unknown primary origin. Previously described diagnostic and prognostic markers were found to be expressed by the appropriate GCT subtype (AFP, POU5F1, POV1, CCND2, and KIT). Several additional differentially expressed genes were identified in teratomas (EGR1 and MMP7), yolk sac tumors (PTPN13 and FN1), and seminomas (NR6A1, DPPA4, and IRX1). Dynamic computation of interaction networks and mapping to existing pathways knowledge databases revealed a potential role of EGR1 in p21-induced cell cycle arrest and intrinsic chemotherapy resistance of mature teratomas.
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PMID:Gene expression profiling differentiates germ cell tumors from other cancers and defines subtype-specific signatures. 1630 58


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