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)

Herpes simplex virus type 1 (HSV-1) infection induces expression of the human immunodeficiency virus type 1 (HIV-1) provirus in the chronically infected T-cell line ACH-2. The HSV-1-mediated induction correlates with the appearance of two NF-kappa B-specific proteins of 55 and 85 kDa in the nucleus and with the binding of 50-kDa nuclear protein to the LBP-1 binding site of the untranslated leader sequence of the HIV-1 long terminal repeat. The HSV-1-induced LBP-1 binding protein, designated HLP-1, is present exclusively in HSV-1-infected, but not in phorbol-12-myristate-13-acetate- or tumor necrosis factor alpha-treated ACH-2 cells. Both the NF-kappa B and LBP-1 target sequences, when inserted either alone or together 5' of a heterologous minimal promoter (thymidine kinase), confer inducibility by HSV-1 infection in a transient transfection assay. Thus, it appears that the HSV-1-mediated activation of HIV-1 provirus is brought about by the binding of both NF-kappa B and HLP-1 specific proteins to two distinct regions of HIV-1 long terminal repeat.
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PMID:Herpes simplex virus type 1-mediated induction of human immunodeficiency virus type 1 provirus correlates with binding of nuclear proteins to the NF-kappa B enhancer and leader sequence. 131 71

The epidermal growth factor (EGF) receptor (EGFR) promoter is negatively regulated by thyroid hormone and retinoic acid. This regulation can be mapped to a 36-basepair GC-rich region of the promoter (EGFR P/E) that functions autonomously as a promoter and an enhancer when placed in front of the thymidine kinase gene TATA element. Direct high affinity binding of the thyroid hormone receptor (T3R) to this element requires a nuclear protein. Through ion exchange chromatography and gel filtration of HeLa nuclear extract, this activity was identified as a protein of approximately 67 kilodaltons. This protein did not bind to DNA alone, but greatly augmented T3R binding to the EGFR P/E sequence in gel mobility shift and DNA precipitation assays. When combined with the T3R auxillary protein (TRAP), the T3R migrated as a larger complex on the DNA. Chemical cross-linking identified this complex as a heterodimer between T3R and TRAP. T3R-TRAP binds to a 7-basepair site in the EGFR P/E (GGGACTC) that has weak homology to a consensus thyroid response element half-site. Thus, on this element, T3R-TRAP heterodimers contact the DNA primarily on a single site that comprises an inhibitory thyroid response element.
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PMID:A nuclear protein is required for thyroid hormone receptor binding to an inhibitory half-site in the epidermal growth factor receptor promoter. 158 25

In the proviral DNA of mouse mammary tumor virus (MMTV), sequences up to approximately equal to 200 base-pairs from the RNA start site are required for stimulation of transcription by glucocorticoid hormones in cultured cells. A total of 26 mutant plasmids with clustered point mutations or small deletions in the hormone control region of the MMTV long terminal repeat were constructed, linked to the coding portion of the Herpes simplex virus thymidine kinase gene, and introduced by transfection into LTK- cells. Transcription from mutant DNA in the presence or absence of hormone was quantified by S1 nuclease protection assays. Our analysis revealed the presence of at least three control elements that affect the extent of transcription stimulation by glucocorticoid hormones: (1) a distal element, between -181 and -172 base-pairs from the RNA initiation site. Linker scanning mutants in this segment have a reduction of up to 20-fold in the hormone response with respect to wild type. (2) An element around position -120, defined by a mutation of 4 base-pairs between -121 and -117, which causes a fivefold reduction. (3) An element from approximately equal to -78 to -70, defined by a mutant with also a roughly fivefold lower stimulation. The first two are included in areas that have been shown by others to interact in vitro with hormone-receptor complexes; the last one overlaps the in vitro binding site of a nuclear protein factor. A mutant lacking all three elements (-193 to -70) is completely non-inducible by glucocorticoids. Together with earlier results obtained with 5' deletion mutants, the data show that the largest contribution to the stimulatory response is made by the distal element, which however does require the presence of both more-proximal ones for the response to be maximal. In the absence of the distal one, the two proximal elements together produce a residual stimulation in the order of 5 to 10% of wild type, while the -70 element alone is ineffective. In addition, we show that a functional TATA homology is required for maximum stimulation. It appears that transcriptional regulation of MMTV by glucocorticoid hormones is achieved by the concerted action of multiple sequence modules, not all of which correspond to receptor binding sites in vitro.
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PMID:Distinct sequence elements involved in the glucocorticoid regulation of the mouse mammary tumor virus promoter identified by linker scanning mutagenesis. 302 41

The c-mos proto-oncogene product, Mos, is a serine/threonine kinase that can activate ERK1 and 2 mitogen-activated protein (MAP) kinases by direct phosphorylation of MAPK/ERK kinase (MEK). ERK activation is essential for oncogenic transformation of NIH 3T3 cells by Mos. In this study, we examined how mitogenic and oncogenic signalling from the Mos/MEK/ERK pathway reaches the nucleus to activate downstream target genes. We show that c-Fos (the c-fos protooncogene product), which is an intrinsically unstable nuclear protein, is metabolically highly stabilized, and greatly enhances the transforming efficiency of NIH 3T3 cells, by Mos. This stabilization of c-Fos required Mos-induced phosphorylation of its C-terminal region on Ser362 and Ser374, and double replacements of these serines with acidic (Asp) residues markedly increased the stability and transforming efficiency of c-Fos even in the absence of Mos. Moreover, activation of the ERK pathway was necessary and sufficient for the c-Fos phosphorylation and stabilization by Mos. These results indicate that c-Fos undergoes stabilization, and mediates at least partly the oncogenic signalling, by the Mos/MEK/ERK pathway. The present findings also suggest that, in general, the ERK pathway may regulate the cell fate and function by affecting the metabolic stability of c-Fos.
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PMID:The Mos/MAP kinase pathway stabilizes c-Fos by phosphorylation and augments its transforming activity in NIH 3T3 cells. 758 33

Serum stimulation of resting cells is mediated at least in part at the transcriptional level by the activation of numerous genes among which c-fos constitutes a model. Serum response factor (SRF) forms a ternary complex at the c-fos serum response element (SRE) with an accessory protein p62TCF/Elk-1. Both proteins are the targets of multiple phosphorylation events and their role is still unknown in the amino terminus of SRF. While the transcriptional activation domain has been mapped between amino acids 339 and 508, the DNA-binding and the dimerization domains have been mapped to between amino acids 133-235 and 168-235, respectively, no role has been proposed for the amino-terminal portion of the molecule. We demonstrate in the present work that amino acids 95 to 100 contain a stretch of basic amino acids that are sufficient to target a reporter protein to the nucleus. Moreover, this sequence appears to be the only nuclear localization signal operating in SRF. Finally, whereas the global structure around this putative nuclear location signal is reminiscent of what is found in the SV40 T antigen, the casein kinase II phosphorylation site does not determine the rate of cyto-nuclear protein transport of this protein.
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PMID:Nuclear import of serum response factor (SRF) requires a short amino-terminal nuclear localization sequence and is independent of the casein kinase II phosphorylation site. 769 2

Cell kinetic data are an important adjunct to histologically based tumor classifications and provide reliable information about future tumor behaviour. The growth fraction of 62 transitional cell carcinomas was assessed using Ki-67 and PCNA (Proliferating cell nuclear antigen/cyclin) immunostainings. Ki-67 recognises an unknown nuclear antigen expressed in dividing cells and requires the use of frozen sections. PCNA, a non histone nuclear protein, identifies proliferating cells within fixed, embedded tissue sections. The percentage of labeled cells was expressed as the labeling index (LI). The median LI in normal urothelium and transitional cell carcinoma were 0.5% and 8%, respectively for Ki-67, and 1.5% and 12% for PCNA. A general agreement between indices of cell proliferation and histological grade and stage was demonstrated. Although some discrepancies were observed, there was a strong correlation between Ki-67 and PCNA Lis (r = 0.8308, P < 0.01). In addition, tumor EGFR positive had PCNA values greater than those found in cancer EGFR negative (P = 0.01). These findings suggest that immunohistochemical nuclear labeling with anti-PCNA on routinely processed tissue is a simple technique for the assessment of transitional cell carcinomas.
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PMID:PCNA/cyclin expression in transitional cell carcinomas of the human bladder: its correlation with Ki-67 and epidermal growth factor receptor immunostainings. 793 59

Constant denaturant gel electrophoresis (CDGE) was used to screen 179 breast carcinomas for mutations in the conserved regions of the TP53 gene (exons 5 through 8). Mutations were found in 35 of 163 primary tumours (21%) and in 5 of 16 metastases (31%) and resided predominantly in exon 7. The majority of the mutations were G:C-->A:T transitions. Immunohistochemistry demonstrated nuclear accumulation of p53 protein in 35 of 162 primary tumours (22%) and in four of 15 metastases (27%). TP53 mutation was strongly associated with nuclear accumulation of p53 protein. In total 42 of 163 primary tumours (26%) and 5 of 16 metastases (31%) were demonstrated to contain TP53 alterations (mutation and/or nuclear protein accumulation). TP53 alteration in primary tumour was significantly associated with the following parameters: positive node status, T status > 1, negative oestrogen receptor status, negative progesterone receptor status, presence of ERBB2 gene amplification, and invasive ductal histology. Furthermore, there were statistically significant associations, independent of other prognostic factors, between TP53 alterations in primary tumour and disease-free and overall survival.
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PMID:Prognostic significance of TP53 alterations in breast carcinoma. 810 35

In 68 cases of surgically resected gastric carcinomas, expression of human epidermal growth factor (EGF) and its receptor (EGFR) were examined immunohistologically using the Avidin-Biotin Peroxidase Complex Method, and their relation with DNA contents and nuclear protein synthesis in the tumor progression were studied by measuring DNA ploidy patterns and nucleolar organizer regions (NORs), respectively with cytofluorometry and AgNO3 stain method. EGF and EGFR expression were respectively found only in 2 (7%) and 1 (4%) in 28 early cancers, and significantly increased in advanced cancers, 25 (63%) and 9 (23%) out of 40 cases. The ratio of aneuploid tumor and the NORs numbers per tumor cell also increased in advanced cancers, compared with in early cancers. EGF and EGFR respectively expressed in 19 (51%) and 9 (23%) in 37 aneuploid cancers, significantly more frequent than 8 (26%) and 1 (3%) in 31 diploid cancers. In the EGF-positive tumors, the NORs numbers showed 4.11 +/- 0.72, significantly higher than 2.68 +/- 0.61 in the EGF-negative tumors. These results suggested that expression of EGF and EGFR in the gastric carcinomas increases during the tumor progression from the early to advanced stage, stimulates synthesis of DNA and nuclear protein, and consequently enhances (strengthens, heightens, or intensifies) the proliferative activity of the tumors.
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PMID:[Expression of human epidermal growth factor and its receptor of the gastric carcinomas with special reference to DNA ploidy patterns and nucleolar organizer regions]. 817 99

A patient with liver cirrhosis who progressed to hepatocellular carcinoma was found to develop novel antinuclear antibodies. The serum was used to isolate full-length cDNA clones encoding related proteins of 530 amino acids (representative clone HCC1.4) and 524 amino acids (representative clone HCC1.3). Affinity-purified antibodies eluted from recombinant proteins recognized a 64-kD nuclear protein in Western blotting and decorated the nucleoplasm in a speckled-network fashion in immunofluorescence, colocalizing with antibodies to pre-mRNA splicing factor SC35 and uridine-rich small nuclear RNAs. The deduced amino acid sequence contained an arginine/serine-rich (RS) domain and three-ribonucleoprotein consensus sequence domains, two classes of motifs present in several splicing factors. A repeating octapeptide of Arg-Ser-Arg-Ser-Arg(Lys)-Glu(Asp)-Arg-Lys(Arg) was present in RS region of HCC1. This octapeptide sequence called RS-ERK motif was also found in splicing factors U2AF 35- and 65-kD proteins and 70-kD U1 small nuclear ribonucleoprotein. The molecular features and immunolocalization data suggest that the HCC1 autoantigen may be associated with splicing activities and are consistent with observations that autoantibody responses frequently target molecules involved in important cellular biosynthetic functions.
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PMID:Novel nuclear autoantigen with splicing factor motifs identified with antibody from hepatocellular carcinoma. 822 58

Overexpression and/or amplification of the HER2/neu gene has been shown in roughly 30% of breast cancer patients. Increased levels of HER2/neu mRNA in some breast cancer cell lines is partially caused by increased gene transcription. In MDA-MB453 human breast cancer cells, an activated trans-acting factor is involved in the increased transcription of HER2/neu by mediating its effects through a specific DNA region in the HER2/neu promoter. A methylation interference experiment showed a novel sequence for protein-DNA interactions. Three polypeptides of approximately 110, 70, and 35 kD interact with this DNA element. This region of the human HER2/neu promoter is highly conserved in the rat and mouse promoters and was shown to be capable of mediating transcriptional trans-activation in HER2/neu-overexpressing MDA-MB453 cells while having little effect in a control cell line that expresses basal levels of HER2/neu. Knowledge on interactions between this DNA element and nuclear protein factors may help us better understand the molecular mechanisms regulating HER2/neu overexpression in breast cancer cells.
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PMID:Identification of a specific DNA region required for enhanced transcription of HER2/neu in the MDA-MB453 breast cancer cell line. 883 33


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