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

We have isolated a genomic clone containing the mouse neu gene. The 5' end of the mouse neu gene was localized by Southern analysis, subcloned and characterized. DNA sequence analysis revealed that the promoter region is 67% G+C-rich and lacks a TATA box, although a CAAT box is present. By sequence comparison, we identified several consensus recognition sequences for general transcription factors such as Sp1, E4TF1, AP2, OTF-1 and GCF, as well as recognition sequences for RVF, E1A and GTG, which have recently been identified in the rat neu promoter. Functional promoter activity was demonstrated by the ability of the promoter to drive transcription of the bacterial chloramphenicol acetyltransferase gene. Using a series of 5'-end deletion mutants, we have identified multiple positive and negative cis-acting elements that regulate mouse neu gene transcription.
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PMID:Cloning and characterization of the mouse neu promoter. 134 55

In an attempt to study potential feedback regulation of the neu oncogene, we have found that the neu oncogene product specifically represses its own promoter activity. Deletion analysis indicated a 140-bp region (nucleotides -312 to -173 relative to the ATG initiation codon) in the rat neu promoter responsible for neu autorepression. Gel shift assays and methylation interference analysis further demonstrated that a GGTGGGGGGG sequence (nucleotides -243 to -234 relative to the ATG initiation codon) in this 140-bp region interacts with specific protein complexes. The GGTGGGGGGG sequence (GTG element), which functions as an enhancer, is sufficient to cause neu-mediated repression in a heterologous promoter. Furthermore, it produces different gel shift patterns with nuclear extracts from neu-transformed cell lines and their parental lines, suggesting that a transcriptional factor(s) interacting with this enhancer element has been perturbed by the introduction of neu. Taken together, the data presented in this report show that (i) the neu oncogene product autorepresses its own promoter, (ii) the neu promoter contains a novel enhancer, and (iii) neu autorepression is mediated through this enhancer, likely by inhibition of the enhancer activity.
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PMID:Negative autoregulation of the neu gene is mediated by a novel enhancer. 135 Mar 24

The ras gene product (p21) is a GTP-binding protein and has been thought to transduce signals regulating proliferation or differentiation of cells. Like other GTP-binding proteins, p21.GTP is an active conformation, which can transduce the signals downstream, whereas p21.GDP is an inactive one. Recently, we have shown that p21.GTP levels increased in cells treated with fetal bovine serum or platelet-derived growth factor to initiate DNA synthesis. In this paper, we report that epidermal growth factor can also increase the amounts of p21.GTP in the cells. Effects of epidermal growth factor and platelet-derived growth factor are not additive. In contrast, mutant [Val12]p21, which has transforming activity, responded neither to platelet-derived growth factor nor to epidermal growth factor. We also found that the ratio of p21.GTP to p21.GDP increased 3- to 4-fold in transformants carrying activated erbB-2/neu or v-src oncogenes. These results strongly suggest an important role of p21 in transduction of signals for both normal proliferation and malignant transformation through growth factor receptors with tyrosine kinase activity or related oncogene products.
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PMID:Accumulation of p21ras.GTP in response to stimulation with epidermal growth factor and oncogene products with tyrosine kinase activity. 214 78

The neu oncogene is frequently overexpressed in breast, ovarian and lung cancers, and its overexpression correlates with poor disease prognosis. The exact mechanism of deregulation of neu expression is not well understood. Our previous studies indicate that the tumor suppressor retinoblastoma gene product, Rb, represses transcription of neu through the GTG enhancer (-243 to -234 relative to initiation of translation site of rat neu). We carried out further deletion analysis of the regulatory sequences of neu and found that Rb also represses neu close to transcription initiation sites (-172 to -79). Bal 31 deletions downstream of nucleotide -172 show that the sequence TCGAGGAA (-172 to -165) is important for efficient transcription from the neu promoter and also for repression by Rb. Rb mutants with mutations in the large T/E1a binding domain repress transcription from transcription initiation sites but not the GTG enhancer, suggesting that Rb modulates different regions of the regulatory sequence of neu by different pathways. The net effect of the Rb mutants is to repress not only transcription but also the transforming activity of activated neu in focus-forming assays. Thus, one mechanism whereby Rb may act as a tumor suppressor is to repress transcription of the strongly transforming neu oncogene.
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PMID:The retinoblastoma gene product, Rb, represses neu expression through two regions within the neu regulatory sequence. 790 32

The transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu is frequently overexpressed in DCIS but is less common in IBC, thereby suggesting additional requirements for transformation. To identify genes capable of cooperating with HER2/neu to fully transform mammary epithelial cells, we used an insertional mutagenesis screen on cells isolated from wild-type neu expressing mice and identified the E3 ligase HACE1 as HER2 cooperative tumor suppressor gene. Loss of HACE1 expression is commonly seen in clinical breast cancer data sets. HACE1 downregulation in normal human mammary epithelial cells (HMECs) results in the accumulation of the activated GTP-bound Rac1 partially transforming these cells. Overexpression of HER2 activates Rac1, which further accumulates upon HACE1 loss resulting in Rac1 hyperactivation. Although the knockdown of HACE1 or overexpression of HER2 alone in HMECs is not sufficient for tumorigenesis, HER2 overexpression combined with HACE1 downregulation fully transforms HMECs resulting in robust tumor formation. The pharmaceutical interference of Rac function abrogates the effects of HACE1 loss both in vitro and in vivo, resulting in marked reduction in tumor burden. Our work supports a critical role for HACE1 in breast cancer progression and identifies patients that may benefit from Rac-targeted therapies.
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PMID:Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression. 2565 79