Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:040116 (histone)
 44,835 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of herpes simplex virus (HSV) thymidine kinase (TK) gene transcription (pHSV-106, pML-BPV-TK4) by DNA methylation is an indirect effect, which occurs with a latency period of approximately equal to 8 hr after microinjection of the DNA into TK- rat 2 and mouse LTK- cells. We have strong evidence that chromatin formation is critical for the transition of the injected DNA from methylation insensitivity to methylation sensitivity. Chromatin was reconstituted in vitro by using methylated and mock-methylated HSV TK DNA and purified chicken histone octamers. After microinjection, the methylated chromatin was always biologically inactive, as tested by autoradiography of the cells after incubation with [3H]thymidine and by RNA dot blot analysis. However, in transformed cell lines, reactivation of the methylated chromatin occurred after treatment with 5-azacytidine. Furthermore, integration of the TK chromatin into the host genome is not required to block expression of the methylated TK gene. Mouse cells that contained the pML-BPV-TK4 chromatin permanently in an episomal state also did not support TK gene expression as long as the TK DNA remained methylated.
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PMID:Chromatin structure is required to block transcription of the methylated herpes simplex virus thymidine kinase gene. 302 68

Cells expressing the herpes simplex-thymidine kinase (HS-TK) gene as a consequence of retroviral transduction, as well as TK-negative (TK-) bystander cells, can be killed by treatment with ganciclovir (GCV). In vitro, this "bystander effect," has been attributed to metabolic cooperation through gap junctions or to the uptake of apoptotic vesicles. We show that GCV treatment kills TK-negative U-87 glioma cells cocultured with cells that express TK (TK+) but that have lost the capacity for releasing retroviral particles. A photometric enzyme immunoassay identifies histone-associated DNA fragments, typical of apoptosis, in the cytosol of GCV-treated TK+ cells, and apoptotic features are also demonstrated by ultrastructural studies. Northern blot analysis and the reverse transcription polymerase chain reaction (PCR) show that connexin 43, a major constituent of gap junctions, is expressed in TK+ and U-87 cells. The size of U-87 tumors in nude mice subsequently injected with TK+ cells and GCV is not significantly different than in untreated animals; whereas, after injecting 1:1 mixtures of U-87 and TK+ cells, GCV treatment only causes a temporary regression of tumor growth. On the contrary, when the injected mixtures contain PA317.STK.SBA (a retroviral producer cell line that can transduce efficiently the HS-TK gene) and U-87 cells, tumors are destroyed effectively by GCV treatment. Thus, an experimental setting in which U-87 gliomas are matched with cells that are able to express, but not to transduce, the HS-TK gene indicates that the bystander effect kills U-87 cells in vitro by mechanisms associated with apoptotic death. In vivo, this effect is not sufficient to restrain the tumor growth taking place in immunodeficient animals.
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PMID:The "bystander effect": association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice. 754 76

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

In the process of positionally cloning a candidate gene responsible for hereditary hemochromatosis (HH), we constructed a 1.1-Mb transcript map of the region of human chromosome 6p that lies 4.5 Mb telomeric to HLA-A. A combination of three gene-finding techniques, direct cDNA selection, exon trapping, and sample sequencing, were used initially for a saturation screening of the 1.1-Mb region for expressed sequence fragments. As genetic analysis further narrowed the HH candidate locus, we sequenced completely 0.25 Mb of genomic DNA as a final measure to identify all genes. Besides the novel MHC class 1-like HH candidate gene HLA-H, we identified a family of five butyrophilin-related sequences, two genes with structural similarity to a type 1 sodium phosphate transporter, 12 novel histone genes, and a gene we named RoRet based on its strong similarity to the 52-kD Ro/SSA lupus and Sjogren's syndrome auto-antigen and the RET finger protein. Several members of the butyrophilin family and the RoRet gene share an exon of common evolutionary origin called B30-2. The B30-2 exon was originally isolated from the HLA class 1 region, yet has apparently "shuffled" into several genes along the chromosome telomeric to the MHC. The conservation of the B30-2 exon in several novel genes and the previously described amino acid homology of HLA-H to MHC class 1 molecules provide further support that this gene-rich region of 6p21.3 is related to the MHC. Finally, we performed an analysis of the four approaches for gene finding and conclude that direct selection provides the most effective probes for cDNA screening, and that as much as 30% of ESTs in this 1.1-Mb region may be derived from noncoding genomic DNA.
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PMID:A 1.1-Mb transcript map of the hereditary hemochromatosis locus. 914 41

Assays for detecting and measuring antinuclear antibodies (ANA) in dogs were compared. They included the indirect immunofluorescence test, using rat liver as substrate, and ELISAs for three nuclear antigens: double-stranded DNA, single-stranded DNA, and histone. There was no correlation between the ANA titre and antibodies to the three nuclear antigens. Analysis of ANA in different arthropathies showed no specific disease association. HEP-2 cells showed no fluorescence reaction with either ANA-positive or ANA-negative dog sera. Western blotting produced too complex a pattern to identify specific antigens. The antigens that reacted with ANA in dogs were not identified; there is either a broad range of reactivities or non-specific binding of immunoglobulins.
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PMID:Analysis and significance of anti-nuclear antibodies in dogs. 916 Apr 32

We have identified a new gene, designated lok (lymphocyte-oriented kinase), that encodes a 966-amino acid protein kinase whose catalytic domain at the N terminus shows homology to that of the STE20 family members involved in mitogen-activated protein (MAP) kinase cascades. The non-catalytic domain of LOK does not have any similarity to that of other known members of the family. There is a proline-rich motif with Src homology region 3 binding potential, followed by a long coiled-coil structure at the C terminus. LOK is expressed as a 130-kDa protein, which was detected predominantly in lymphoid organs such as spleen, thymus, and bone marrow, in contrast to other mammalian members of the STE20 family. LOK phosphorylated itself as well as substrates such as myelin basic protein and histone IIA on serine and threonine residues but not on tyrosine residues, establishing LOK as a novel serine/threonine kinase. When coexpressed in COS7 cells with the known MAP kinase isoforms (ERK, JNK, and p38), LOK activated none of them in contrast to PAK- and GCK-related kinases. These results suggest that LOK could be involved in a novel signaling pathway in lymphocytes, which is distinct from the known MAP kinase cascades.
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PMID:LOK is a novel mouse STE20-like protein kinase that is expressed predominantly in lymphocytes. 927 26

The anti-cancer drug paclitaxel (Taxol) alters microtubule assembly and activates pro-apoptotic signaling pathways. Previously, we and others found that paclitaxel activates endogenous JNK in tumor cells, and the activation of JNK contributes to tumor cell apoptosis. Here we find that paclitaxel activates the prosurvival MEK/ERK pathway, which conversely may compromise the efficacy of paclitaxel. Hence, a combination treatment of paclitaxel and MEK inhibitors was pursued to determine whether this treatment could lead to enhanced apoptosis. The inhibition of MEK/ERK with a pharmacologic inhibitor, U0126, together with paclitaxel resulted in a dramatic enhancement of apoptosis that is four times more than the additive value of the two drugs alone. Enhanced apoptosis was verified by the terminal transferase-mediated dUTP nick end labeling assay, by an enzyme-linked immunosorbent assay for histone-associated DNA fragments, and by flow cytometric analysis for DNA content. Specificity of the pharmacologic inhibitor was confirmed by the use of (a) a second MEK/ERK inhibitor and (b) a transdominant-negative MEK. Enhanced apoptosis was verified in breast, ovarian, and lung tumor cell lines, suggesting this effect is not cell type-specific. This is the first report of enhanced apoptosis detected in the presence of paclitaxel and MEK inhibition and suggests a new anticancer strategy.
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PMID:MEK inhibition enhances paclitaxel-induced tumor apoptosis. 1103 47

Activation of the heregulin/HER2 pathway in oestrogen receptor (ER)-positive breast-cancer cells leads to suppression of oestrogen-receptor element (ERE)-driven transcription and disruption of oestradiol responsiveness, and thus contributes to progression of tumours to more invasive phenotypes. Here we report the identification of metastatic-associated protein 1 (MTA1), a component of histone deacetylase (HDAC) and nucleosome-remodelling complexes, as a gene product induced by heregulin-beta1 (HRG). Stimulation of cells with HRG is accompanied by suppression of histone acetylation and enhancement of deacetylase activity. MTA1 is also a potent corepressor of ERE transcription, as it blocks the ability of oestradiol to stimulate ER-mediated transcription. The histone-deacetylase inhibitor trichostatin A blocks MTA1-mediated repression of ERE transcription. Furthermore, MTA1 directly interacts with histone deacetylase-1 and -2 and with the activation domain of ER-alpha. Overexpression of MTA1 in breast-cancer cells is accompanied by enhancement of the ability of cells to invade and to grow in an anchorage-independent manner. HRG also promotes interaction of MTA1 with endogenous ER and association of MTA1 or HDAC with ERE-responsive target-gene promoters in vivo. These results identify ER-mediated transcription as a nuclear target of MTA1 and indicate that HDAC complexes associated with the MTA1 corepressor may mediate ER transcriptional repression by HRG.
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PMID:Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor. 1114 23

Changes in gene expression are thought to be involved in neuronal plasticity associated with learning and memory. Although acetylation of lysine residues on histones by histone acetyltransferases (HAT) is an obligatory component of transcription, HAT activity has been largely ignored in studies of the nervous system. We developed a new model for studying novel taste learning using novel solid food presentation to nondeprived animals. Using this behavioral paradigm, we investigated short- and long-term regulation of lysine acetyltransferase activity and the ERK/mitogen-activated protein kinase (MAPK)/RSK cascade in insular cortex, a CNS region known to be crucial for the formation of novel taste memories. We observed that novel taste learning elicited biphasic (acute and long-lasting) activation of two distinct lysine acetyltransferase activities along with the ERK/MAPK cascade in insular cortex. In vitro studies revealed that the ERK cascade could regulate the lysine acetylation of a 42 kDa lysine acetyltransferase substrate, suggesting a causal relationship between ERK activation and lysine acetyltransferase activity in insular cortex. Overall, our studies reveal an unanticipated long-lasting activation of insular cortex signal transduction cascades in novel taste learning. Furthermore, our studies suggest the hypothesis that acute and long-term ERK activation and lysine-histone acetyltransferase activation may play a role in regulating gene expression in single-trial learning and long-term memory formation.
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PMID:Increased histone acetyltransferase and lysine acetyltransferase activity and biphasic activation of the ERK/RSK cascade in insular cortex during novel taste learning. 1133 68

Deregulation of the HER2 oncogene occurs in 30% of human breast cancers and correlates with poor prognosis and increased propensity for metastasis. Since the molecular basis of HER2 overexpression in human cancers is not known, we sought to determine whether chromatin remodeling pathways are involved in the regulation of HER2 expression. We report that compared with breast cancer cells expressing a low level of HER2, HER2-overexpressing breast cancer cells contained significantly higher levels of acetylated and phosphorylated histone H3, and acetylated histone H4 associated with the HER2 promoter. Decreased recruitment of histone deacetylases in the promoter is also noted in the HER2-overexpressing cell. The association of acetylated histone H4 with HER2 gene chromatin and HER2 expression in breast cancer cells was upregulated by an inhibitor of histone deacetylases. Treatment with histone deacetylase inhibitor also reduced the association of histone deacetylase-1 and -2 with the HER2 promoter. In addition, the tumor promoters 12-O-tetradecanoylphorbol-13-acetate and okadaic acid stimulated the association of phosphorylated histone H3 on serine 10 with the HER2 promoter and also stimulated HER2 expression. These findings identify histone acetylation and histone phosphorylation as novel regulatory modifications that target HER2 gene chromatin, and suggest that elevated levels of these chromatin-relaxing components in the vicinity of the HER2 gene promoter may constitute an important non-genomic mechanism of HER2 overexpression in human breast cancer.
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PMID:Dynamic chromatin remodeling on the HER2 promoter in human breast cancer cells. 1168 64


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