Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rat neu protooncogene encodes a 185 kD transmembrane protein (p185neu), which is a member of the epidermal growth factor receptor (EGFr) family. In searching for the signaling transducer of p185neu by using a two-hybrid selection system, we found, surprisingly, that the cytoplasmic domain of p185neu, when fused to the DNA-binding domain of GAL4 (amino acids 1-147), functioned as a transcriptional activator. We subsequently observed nuclear localization of p185neu. Interestingly, nuclear p185neu has a much higher extent of tyrosine phosphorylation than its nonnuclear counterpart. Our results suggest that a transmembrane receptor tyrosine kinase may enter the nucleus and be involved in transcriptional activation. This novel finding unveils a clue in the understanding of the mechanism of receptor tyrosine kinase-mediated signal transduction.
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PMID:Nuclear localization of p185neu tyrosine kinase and its association with transcriptional transactivation. 794 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

Overexpression of the HER2/Neu receptor is correlated to a poor prognosis in tumor patients and leads to stimulation of mitogen-activated protein kinase (MAPK) signaling pathways, which in turn activate transcription factors, such as the ETS protein ER81. Here, we have analyzed whether, on the other hand, ER81 may regulate the Her2/neu gene. Indeed, ER81, together with its co-activators, p300 and CBP, activates the Her2/neu promoter, and this activation is enhanced upon stimulation of MAPK pathways as well as by oncogenic HER2/Neu protein. Furthermore, ER81 interacts with one ETS binding site in the Her2/neu promoter, whose mutation decreases ER81-mediated transcription. Activation of the Her2/neu promoter is also diminished upon mutation of MAPK-dependent phosphorylation sites in ER81 or upon deletion of ER81 transactivation domains. In addition, the ER81 DNA-binding domain on its own functions as a dominant-negative molecule, effectively repressing any stimulation of the Her2/neu promoter. Altogether, our results show that ER81 is a component of a positive regulatory feedback loop, in which the HER2/Neu protein activates ER81, as well as p300/CBP via MAPKs causing the upregulation of the Her2/neu gene.
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PMID:Regulation of Her2/neu promoter activity by the ETS transcription factor, ER81. 1211 28

The recently identified TGF-beta-inducible early gene 3 (Tieg3) belongs to the gene family of Sp1/Klf-like transcription factors and is upregulated immediately after TGF-beta treatment. To explore the molecular mechanisms of Tieg3-mediated transcriptional control, GAL4-based luciferase assays were performed in order to determine regulatory domains within the Tieg3 protein. Using EGFP-fusion proteins, we monitored the intracellular localization and mapped putative nuclear localization signals (NLS). We provide evidence that the amino-terminus of Tieg3 is essential to repress the transcription and that the loss of the mSin3A interacting domain (SID) disrupts the repressive effects of Tieg3 in the oligodendroglial cell line OLI-neu. Herein we also demonstrate that the zinc finger containing DNA-binding domain (DBD) alone is able to activate the transcription of a reporter gene. Sequence analysis of the zinc finger region revealed no similarities to known activation domains. Analysis of the subcellular localization disclosed Tieg3 as a nuclear protein. Further, we identified the DBD as being essential for the nuclear localization of Tieg3. We detected two closely located putative bipartite NLS within the second and third zinc finger, which are conserved among the members of the Tieg family of proteins. Together these results may help to increase the understanding of Tieg3-mediated transcriptional control and to characterize this TGF-beta-induced Sp1/Klf-like transcription factor.
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PMID:Functional domains of the TGF-beta-inducible transcription factor Tieg3 and detection of two putative nuclear localization signals within the zinc finger DNA-binding domain. 1725 42