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)

Several mechanisms are employed by members of transcription factor families to achieve sequence-specific DNA recognition. In this study, we have investigated how members of the ETS-domain transcription factor family achieve such specificity. We have used the ternary complex factor (TCF) subfamily as an example. ERK2 mitogen-activated protein kinase stimulates serum response factor-dependent and autonomous DNA binding by the TCFs Elk-1 and SAP-la. Phosphorylated Elk-1 and SAP-la exhibit specificities of DNA binding similar to those of their isolated ETS domains. The ETS domains of Elk-1 and SAP-la and SAP-2 exhibit related but distinct DNA-binding specificities. A single residue, D-69 (Elk-1) or V-68 (SAP-1), has been identified as the critical determinant for the differential binding specificities of Elk-1 and SAP-1a, and an additional residue, D-38 (Elk-1) or Q-37 (SAP-1), further modulates their DNA binding. Creation of mutations D38Q and D69V is sufficient to confer SAP-la DNA-binding specificity upon Elk-1 and thereby allow it to bind to a greater spectrum of sites. Molecular modelling indicates that these two residues (D-38 and D-69) are located away from the DNA-binding interface of Elk-1. Our data suggest a mechanism in which these residues modulate DNA binding by influencing the interaction of other residues with DNA.
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PMID:Determinants of DNA-binding specificity of ETS-domain transcription factors. 866 49

The paired box transcription factor Pax-5 (B-cell-specific activator protein) is a key regulator of lineage-specific gene expression and differentiation in B-lymphocytes. We show that Pax-5 functions as a cell type-specific docking protein that facilitates binding of the early B-cell-specific mb-1 promoter by proteins of the Ets proto-oncogene family. Transcriptional activity of the mb-1 promoter in pre-B-cells is critically dependent on binding sites for Pax-5:Ets complexes. Ternary complex assembly requires only the Pax-5 paired box and ETS DNA-binding domains. Mutation of a single base pair in the ternary complex binding site allows for independent binding by Ets proteins but, conversely, inhibits the binding of Pax-5 by itself. Strikingly, the mutation reverses the pattern of complex assembly: Ets proteins recruit Pax-5 to bind the mutated sequence. Recruitment of Net and Elk-1, but not SAP1a, by Pax-5 defines a functional difference between closely related Ets proteins. Replacement of a valine (V68) in the ETS domain of SAP1a by aspartic acid (as found in c-Ets-1, Elk-1, and Net) enhanced ternary complex formation by more than 60-fold. Together, these observations define novel transcription factor interactions that regulate gene expression in B cells.
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PMID:Pax-5 (BSAP) recruits Ets proto-oncogene family proteins to form functional ternary complexes on a B-cell-specific promoter. 880 14

TEL is a novel member of the ETS family of transcriptional regulators which is frequently involved in human leukemias as the result of specific chromosomal translocations. We show here by co-immunoprecipitation and GST chromatography analyses that TEL and TEL-derived fusion proteins form homotypic oligomers in vitro and in vivo. Deletion mutagenesis identifies the TEL oligomerization domain as a 65 amino acid region which is conserved in a subset of the ETS proteins including ETS-1, ETS-2, FLI-1, ERG-2 and GABP alpha in vertebrates and PNTP2, YAN and ELG in Drosophila. TEL-induced oligomerization is shown to be essential for the constitutive activation of the protein kinase activity and mitogenic properties of TEL-platelet derived growth factor receptor beta (PDGFR beta), a fusion oncoprotein characteristic of the leukemic cells of chronic myelomonocytic leukemia harboring a t(5;12) chromosomal translocation. Swapping experiments in which the TEL oligomerization domain was exchanged by the homologous domains of representative vertebrate ETS proteins including ETS-1, ERG-2 and GABP alpha show that oligomerization is a specific property of the TEL amino-terminal conserved domain. These results indicate that the amino-terminal domain conserved in a subset of the ETS proteins has evolved to generate a specialized protein-protein interaction interface which is likely to be an important determinant of their specificity as transcriptional regulators.
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PMID:A domain of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface essential to the mitogenic properties of the TEL-PDGFR beta oncoprotein. 900 69

Chromosomal abnormalities involving the short arm of chromosome 12 have been frequently observed in a broad spectrum of hematological malignancies. Recently, a gene located in this chromosomal region and implicated in leukemogenesis was identified. The gene, called ETV6 (previously known as TEL) is a new member of the ETS family, a group of genes thought to act as transcriptional activators. The gene spans 240 kb and consists of eight exons coding for a helix-loop-helix (HLH) and a DNA-binding domain. ETV6 was originally identified in a t(5;12)(q33;p13) occurring in a chronic myelomonocytic leukemia (CMML). Recent reports, however, show its involvement in a growing number of translocations associated with myeloid as well as lymphoid leukemias. At the molecular level fusions of ETV6 with PDGFRB (5q33), ABL (9q34), MNI(22q11) and AML1(21q22) have already been identified. Analysis of these chimeric proteins indicates that distinct domains of ETV6 can be involved in different fusion products, thus ETV6 can provide transcriptional and dimerization properties for partner genes, or the gene itself can act as an altered transcriptional factor. At least two clinico-pathological entities associated with ETV6 rearrangements have emerged as distinct disorders. The first one is a chronic myeloid malignancy characterized by t(5;12)(q33;p13), monocytosis and/or eosinophilia. The second entity is a type of childhood acute lymphoblastic leukemia (ALL) hallmarked by t(12;21)(p13;q22), and is shown to be the most frequent but cytogenetically largely undetectable chromosomal anomaly in childhood ALL.
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PMID:ETV6 gene rearrangements in hematopoietic malignant disorders. 903 Nov 9

The >30 known members of the Ets multigene family of transcriptional regulators are increasingly being recognized for their involvement in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of target gene expression. Identifiable primarily by their 85 amino acid ETS DNA-binding domain and dispersed across all metazoan lineages into distinct subfamilies, Ets genes also produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain, suggesting that their oncogenic potential is determined by the program of target genes they regulate. Searching for Ets factors that regulate expression of the HER2/neu (c-erbB2) oncogene in human breast cancer, we identified a new epithelium-restricted Ets encoding an ETS domain homologous to the Drosophila E74/human Elf-1 subfamily, an amino-terminal region (A-region or Pointed domain) homologous to the distantly related Ets-1 subfamily, and a serine-rich box homologous to the transactivating domain of the lymphocyte-restricted High Mobility Group (HMG) protein, SOX4. Recombinant protein encoded by ESX (for epithelial-restricted with serine box) exhibits Ets-like DNA binding specificity in electrophoretic mobility shift assays and, in transient transfection assays, transactivates Ets-responsive promoter elements including that found in the HER2/neu oncogene. ESX is located at chromosome 1q32 in a region known to be amplified in 50% of early breast cancers, is heregulin-inducible and overexpressed in HER2/neu activated breast cancer cells. Tissue hybridization suggests that ESX becomes overexpressed at an early stage of human breast cancer development known as ductal carcinoma in situ (DCIS).
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PMID:ESX: a structurally unique Ets overexpressed early during human breast tumorigenesis. 912 54

The ternary complex factor (TCF) subfamily of ETS-domain transcription factors form ternary complexes with the serum response factor (SRF) and the c-fos SRE. Extracellular signals are relayed via MAP kinase signal transduction pathways through the TCF component of the ternary complex. Protein-protein interactions between TCFs and SRF play an essential role in formation of this ternary complex. A 30 amino acid sequence encompassing the TCF B-box is sufficient to mediate interactions with SRF. In this study we have identified amino acids which are critical for this interaction and derived a molecular model of the SRF binding interface. Alanine scanning of the Elk-1 B-box reveals five predominantly hydrophobic residues which are essential for binding to SRF and for ternary complex formation in vitro and in vivo. These amino acids are predicted to lie on one face of an alpha-helix. Peptides encompassing the B-box retain biological activity and have helix-forming propensity. alpha-Helix and ternary complex formation is disrupted by the introduction of helix-breaking proline residues. Our results are consistent with a model in which the Elk-1 B-box forms an inducible alpha-helix which presents a hydrophobic face for interaction with SRF. We discuss the wider applicability of our results to similar short protein-protein interaction motifs found in other transcription factors.
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PMID:Molecular characterization of the B-box protein-protein interaction motif of the ETS-domain transcription factor Elk-1. 917 56

HER2/Neu is overexpressed in 25-30% of all human breast cancers as a result of both gene amplification and enhanced transcription. Transcriptional upregulation of HER2/neu leads to a 6-8-fold increased abundance of its mRNA per gene copy and likely results from the elevated activity of transcription factors acting on the HER2/neu promoter. Here we report that transcripts of PEA3, an ETS transcription factor implicated in oncogenesis, were increased in 93% of HER2/Neu-overexpressing human breast tumor samples. Analyses to uncover the molecular basis for elevated PEA3 transcripts in HER2/Neu-positive breast tumors revealed that the HER2/Neu receptor tyrosine kinase initiated an intracellular signaling cascade resulting in increased PEA3 transcriptional activity; transcriptionally-activated PEA3 stimulated HER2/neu and PEA3 gene transcription by binding to sites in the promoters of these genes. PEA3 also activates transcription of genes encoding matrix-degrading proteinases, enzymes required for tumor cell migration and invasion. These findings implicate PEA3 in the initiation and progression of HER2/Neu positive breast cancer, and suggest that PEA3 and signaling proteins affecting its regulation are appropriate therapeutic targets.
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PMID:HER2/Neu and the Ets transcription activator PEA3 are coordinately upregulated in human breast cancer. 938 Apr 3

The activation of MAP kinase (MAPK) signal transduction pathways results in the phosphorylation of transcription factors by the terminal kinases in these cascades. Different pathways are activated by mitogenic and stress stimuli, which lead to the activation of distinct groups of target proteins. The ETS-domain transcription factor Elk-1 is a substrate for three distinct classes of MAPKs. Elk-1 contains a targeting domain, the D-domain, which is distinct from the phosphoacceptor motifs and is required for efficient phosphorylation and activation by the ERK MAPKs. In this study, we demonstrate that members of the JNK subfamily of MAPKs are also targeted to Elk-1 by this domain. Targeting via this domain is essential for the efficient and rapid phosphorylation and activation of Elk-1 both in vitro and in vivo. The ERK and JNK MAPKs use overlapping yet distinct determinants in the D-domain for targeting to Elk-1. In contrast, members of the p38 subfamily of MAPKs are not targeted to Elk-1 via this domain. Our data therefore demonstrate that different classes of MAPKs exhibit differential requirements for targeting to Elk-1.
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PMID:Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. 950 Oct 95

Serum response elements (SREs) play important roles in transforming extracellular signals into specific nuclear responses. The SRE-binding protein, serum response factor (SRF), plays a pivotal role in this process. Several transcription factors have been shown to interact with SRF and thereby create distinct complexes with different regulatory potentials. The ETS domain transcription factor Elk-1 is one such protein and serves to integrate distinct mitogen-activated protein kinase cascades at SREs. Elk-1 uses a short hydrophobic surface presented on the surface of an alpha-helix to interact with SRF. In this study we have used site-directed mutagenesis to identify residues in SRF that comprise the Elk-1 binding surface. The Elk-1 binding surface is composed of residues that lie on a hydrophobic surface-exposed groove located at the junction of the MADS box and C-terminal SAM motif. Different residues are implicated in interactions between SRF and the transcription factor Fli-1, indicating that although some overlap with the Elk-1 binding surface occurs, their interaction surfaces on SRF are distinct. Our data are consistent with the hypothesis that the SRF DNA-binding domain acts as docking site for multiple transcription factors that can bind to small surface-exposed patches within this domain.
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PMID:Interaction of transcription factors with serum response factor. Identification of the Elk-1 binding surface. 955 10

The PEA3 subfamily of ETS-domain proteins play important roles in regulating transcriptional activation and have been implicated in several tumorigenic processes. Here we describe the identification of a further member of this family from zebrafish which most likely represents a homologue of PEA3. A high degree of sequence conservation is observed in the ETS DNA-binding domain and acidic transcriptional activation domain. The DNA binding specificity of zebrafish PEA3 is virtually identical to that exhibited by mammalian family members and is autoregulated by cisacting inhibitory domains. Transcriptional activation by zebrafish PEA3 is potentiated by the ERK MAP kinase and protein kinase A pathways. During embryogenesis, PEA3 is expressed in complex spatial and temporal patterns in both mesodermal somites and ectodermal tissues including the brain, dorsal spinal chord and neural crest. Our characterisation of zebrafish PEA3 furthers our understanding of its molecular function and its expression profile suggests a novel role in cell patterning in the early vertebrate embryo.
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PMID:Molecular characterization of the zebrafish PEA3 ETS-domain transcription factor. 967 18


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