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)

The FMS-like tyrosine kinase 3 (FLT3) gene, belonging to the receptor tyrosine kinase (TK) subclass III family, plays an important role in normal hematopoiesis and is one of the most frequently mutated genes in hematologic malignancies as well as an attractive target for directed inhibition. Activating mutations of this gene, including internal tandem duplication in the juxtamembrane (JM) domain and point mutations in the TK domain, are found in approximately one-third of patients with acute myeloid leukemia and in a smaller subset of patients with acute lymphoblastic leukemia. We report here that FLT3 may contribute to leukemogenesis in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation through generating a fusion gene with the ETS variant gene 6 (ETV6) gene. ETV6 has been reported to fuse to various partner genes, including TK and transcription factors. Both ETV6/FLT3 and reciprocal FLT3/ETV6 transcripts were detected in the patient mRNA by reverse transcriptase-polymerase chain reaction. At the protein level, however, only ETV6/FLT3 products were expressed. Among them, one retains the helix-loop-helix (HLH) oligomerization domain of ETV6 and the JM as well as TK domain of FLT3. FLT3 receptor in leukemic cells might be inappropriately activated through dimerization by HLH domain of ETV6, which consequently interfered with proliferation and differentiation of hematopoietic cells.
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PMID:FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation. 1676 Oct 19

A systematic search in the available scaffolds of the Strongylocentrotus purpuratus genome has revealed that this sea urchin has 11 members of the ets gene family. A phylogenetic analysis of these genes showed that almost all vertebrate ets subfamilies, with the exception of one, so far found only in mammals, are each represented by one orthologous sea urchin gene. The temporal and spatial expression of the identified ETS factors was also analyzed during embryogenesis. Five ets genes (Sp-Ets1/2, Sp-Tel, Sp-Pea, Sp-Ets4, Sp-Erf) are also maternally expressed. Three genes (Sp-Elk, Sp-Elf, Sp-Erf) are ubiquitously expressed during embryogenesis, while two others (Sp-Gabp, Sp-Pu.1) are not transcribed until late larval stages. Remarkably, five of the nine sea urchin ets genes expressed during embryogenesis are exclusively (Sp-Ets1/2, Sp-Erg, Sp-Ese) or additionally (Sp-Tel, Sp-Pea) expressed in mesenchyme cells and/or their progenitors. Functional analysis of Sp-Ets1/2 has previously demonstrated an essential role of this gene in the specification of the skeletogenic mesenchyme lineage. The dynamic, and in some cases overlapping and/or unique, developmental expression pattern of the latter five genes suggests a complex, non-redundant function for ETS factors in sea urchin mesenchyme formation and differentiation.
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PMID:Identification and developmental expression of the ets gene family in the sea urchin (Strongylocentrotus purpuratus). 1699 94

PU.1, a transcription factor of the ETS family, plays a pivotal role in normal hematopoiesis, and particularly in myeloid differentiation. Altered PU.1 function is possibly implicated in leukemogenesis, as PU.1 gene mutations were identified in some patients with acute myeloid leukemia (AML) and as several oncogenic products (AML1-ETO, promyelocytic leukemia-retinoic acid receptor alpha, FMS-like receptor tyrosine kinase 3 internal tandem duplication) are associated with PU.1 downregulation. To demonstrate directly a role of PU.1 in the blocked differentiation of leukemic blasts, we transduced cells from myeloid cell lines and primary blasts from AML patients with a lentivector encoding PU.1. In NB4 cells we obtained increases in PU.1 mRNA and protein, comparable to increases obtained with all-trans retinoic acid-stimulation. Transduced cells showed increased myelomonocytic surface antigen expression, decreased proliferation rates and increased apoptosis. Similar results were obtained in primary AML blasts from 12 patients. These phenotypic changes are characteristic of restored blast differentiation. PU.1 should therefore constitute an interesting target for therapeutic intervention in AML.
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PMID:Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts. 1736 Dec 23

Chromosome structural aberrations giving rise to fusion oncogenes is one of the most common mechanisms in oncogenesis. Although this type of gene rearrangement has long been recognized as a fundamental pathogenetic mechanism in hematologi-cal malignancies and soft-tissue tumors, it has until recently only rarely been described in the common carcinomas. In this review, the existing information on recurrent fusion oncogenes characterizing carcinomas is summarized, namely, the RET and NTRK1 fusion oncogenes in papillary thyroid carcinoma, PAX8-PPARG in follicular thyroid carcinoma, MECT1-MAML2 in mucoepidermoid carcinoma, the TFE3 and TFEB fusion oncogenes in kidney carcinomas, BRD4-NUT in midline carcinomas, ETV6-NTRK3 in secretory breast carcinomas, and TMPRSS2-ETS fusion oncogenes in prostate carcinomas. As in hematological and soft-tissue malignancies, the most common types of genes involved in fusion oncogenes in carcinomas are transcription factors and tyrosine kinases. With a few exceptions, most fusion oncogenes are tumor type specific in carcinomas, as in other cancers. The mechanisms behind the relative specificity of this type of somatic mutation involve the cellular environment influencing the selection of oncogenic fusions, and the oncogenic fusions in turn driving differentiation programs that may alter the cellular environment. The data summarized on different types of carcinomas characterized by fusion oncogenes indicate that the pathogenetic mechanisms involved in epithelial carcino-genesis may be similar to those known to operate in hematological and soft-tissue malignancies, and further anticipates that many more fusion oncogenes await identification in the most common types of human cancer.
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PMID:Recurrent fusion oncogenes in carcinomas. 1742 5

A "bidirectional gene pair" comprises two adjacent genes whose transcription start sites are neighboring and directed away from each other. The intervening regulatory region is called a "bidirectional promoter." These promoters are often associated with genes that function in DNA repair, with the potential to participate in the development of cancer. No connection between these gene pairs and cancer has been previously investigated. Using the database of spliced-expressed sequence tags (ESTs), we identified the most complete collection of human transcripts under the control of bidirectional promoters. A rigorous screen of the spliced EST data identified new bidirectional promoters, many of which functioned as alternative promoters or regulated novel transcripts. Additionally, we show a highly significant enrichment of bidirectional promoters in genes implicated in somatic cancer, including a substantial number of genes implicated in breast and ovarian cancers. The repeated use of this promoter structure in the human genome suggests it could regulate co-expression patterns among groups of genes. Using microarray expression data from 79 human tissues, we verify regulatory networks among genes controlled by bidirectional promoters. Subsets of these promoters contain similar combinations of transcription factor binding sites, including evolutionarily conserved ETS factor binding sites in ERBB2, FANCD2, and BRCA2. Interpreting the regulation of genes involved in co-expression networks, especially those involved in cancer, will be an important step toward defining molecular events that may contribute to disease.
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PMID:Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes. 1744 39

The fate of the vulval cells in Caenorhabditis elegans is specified, at least in part, through a highly conserved RTK/Ras mediated signaling cascade that negatively regulates the activity of the ETS-like transcription factor LIN-1. The Hox gene lin-39 functions downstream of both, the LIN-3/RTK/Ras pathway and LIN-1 and plays a pivotal role in controlling vulva cell competence and induction. Here we show that LET-418, a C. elegans ortholog of the human NuRD component Mi-2, negatively modulates the activity of lin-39. LET-418 interacts in vivo with specific regions in the promoter of lin-39 and this interaction depends on LIN-1. Our data provide evidence for a model in which LIN-1 recruits LET-418/Mi-2 as co-repressor to the promoter of lin-39, thereby restricting its activity to the basal levels required in the vulva precursor cells (VPCs) for normal vulval development. Thus, our data suggest that the interaction between LIN-1 and LET-418/Mi-2 may link RTK/Ras signaling with chromatin remodeling and gene expression.
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PMID:The Mi-2 nucleosome-remodeling protein LET-418 is targeted via LIN-1/ETS to the promoter of lin-39/Hox during vulval development in C. elegans. 1746 68

Elevated expression of the epidermal growth factor (EGF) receptor (EGFR) is detected in human ovarian tumors and is associated with decreased recurrence-free and overall survival. EGFR activation affects tumor progression in part by promoting tumor invasion through the induction of prometastatic matrix metalloproteinases (MMP). PEA3, an ETS family transcription factor, is elevated in advanced and metastatic ovarian cancer and regulates MMPs in various cell types, therefore, we investigated whether PEA3 is required for the EGFR-dependent induction of MMP mRNA. MMP-9 and MMP-14 mRNA levels were selectively increased in response to EGFR activity in ovarian tumor cells. EGFR activation resulted in nuclear accumulation of PEA3 and direct binding of PEA3, but not the related protein ETS-1, to the endogenous MMP-9 and MMP-14 promoters. Furthermore, PEA3 overexpression was sufficient to induce MMP-9 and MMP-14 mRNA, tumor cell migration, and invasion, suggesting that PEA3 is an important contributor to the metastatic phenotype. Additionally, inhibition of PEA3 expression via short interfering RNA reduced the EGF induction of MMP-9 and MMP-14 gene expression by 92% and 50%, respectively, and impaired EGF-stimulated tumor cell invasion. These results suggest that PEA3 is regulated by EGFR and that the elevated PEA3 expression detected in human ovarian cancer may divert cells to a more invasive phenotype by regulating MMP-9 and MMP-14.
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PMID:PEA3 is necessary for optimal epidermal growth factor receptor-stimulated matrix metalloproteinase expression and invasion of ovarian tumor cells. 1747 71

Parathyroid hormone-related protein (PTHrP) is an autocrine/paracrine factor produced by breast cancer cells that is speculated to play a major role in permitting breast cancer cells to grow into the bone microenvironment by stimulating the bone resorption axis. It has been previously shown that EGFR signaling induces the production of PTHrP in several primary and transformed epithelial cell types. Therefore, we investigated the relationship between EGFR and PTHrP gene expression in human breast cancer cells. Of a panel of 7 breast epithelial and cancer cell lines, the osteolytic, EGFR- positive lines (MDA-MB-231 and NS2T2A1) exhibited higher levels of PTHrP transcript expression. Amphiregulin mRNA levels in all lines were approximately 2 orders of magnitude higher than those of TGFalpha or HB-EGF. In the EGFR bearing lines, the receptor was phosphorylated at tyrosine 992 under basal conditions, and the addition of 100 nM amphiregulin did not lead to the phosphorylation of other tyrosine residues typically phosphorylated by the prototypical ligand EGF. Treatment of the EGFR positive lines with the EGFR inhibitor PD153035 and amphiregulin-neutralizing antibodies reduced PTHrP mRNA levels by 50-70%. Stable EGFR expression in the MCF7 line failed to increase basal PTHrP mRNA levels; however, treatment of this cell line with exogenous EGF or amphiregulin increased PTHrP transcription 3-fold. Transient transfection analysis suggests that the MAPK pathway and ETS transcription factors mediate EGFR coupling to PTHrP gene expression. Taken together, it appears that autocrine stimulation of EGFR signaling by amphiregulin is coupled to PTHrP gene expression via EGFR Tyr992 and MAPK, and that this pathway may contribute to PTHrP expression by breast tumor cells.
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PMID:Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells. 1788 47

Elk-1, an ETS domain transcription factor of the TCF (ternary complex factor) subfamily, is known to be involved in the regulation of immediate-early genes such as c-fos upon mitogen activation, and thus commonly implied in cell proliferation. Early growth response-1, Egr-1, which was known to be an immediate-early gene, has recently been shown to be pro-apoptotic for SH-SY5Y neuroblastoma cells. In that respect, it was not clear whether Elk-1 would activate or repress from this promoter, since Elk-1 is mostly associated with proliferation and not apoptosis. In this study, we wanted to address whether Elk-1 activates or represses egr-1 promoter in neuroblastoma cells, and using a combination of RNA interference and reporter analyses, we present evidence that egr-1 gene is repressed by Elk-1 in normally cycling SH-SY5Y neuroblastoma cell line in a SUMO (small ubiquitin-related modifier)-dependent manner, a potential mechanism used by these cells to bypass apoptosis.
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PMID:Wildtype Elk-1, but not a SUMOylation mutant, represses egr-1 expression in SH-SY5Y neuroblastomas. 1843 15

ETS domain transcription factor Elk-1 has been primarily studied in the regulation of genes in response to mitogenic stimuli, however the presence of Elk-1 in axonal projections of largely post-mitotic adult hippocampal sections has been reported. This finding has initially led us to a basic question: how is Elk-1 anchored to neuronal projections? To that end, we have investigated the intracellular localization of Elk-1 and its biochemical interactions with neuronal microtubules in model systems. Our results showed co-localization of Elk-1 with microtubules in hippocampal cultures and SH-SY5Y neuroblastoma cell lines, and have further demonstrated that Elk-1 protein can biochemically interact with microtubules in vitro. Analysis of the protein sequence has indicated many putative microtubule binding domains, with the strongest binding prediction in amino acids 314-325, and our results show that Elk-1 can bind to microtubules through most of these regions, but no interaction was observed through the DNA binding domain, where no putative binding motifs were predicted. We further show that upon serum induction, most of the phospho-Elk-1 translocates to the nucleus, which is independent of translation. We propose that Elk-1 is anchored to neuronal microtubules in resting or unstimulated cells, and upon stimulation is phosphorylated, which relocalizes phospho-Elk-1 to the nucleus in neurons.
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PMID:Elk-1 interacts with neuronal microtubules and relocalizes to the nucleus upon phosphorylation. 1901 29


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