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)

Molecular virology has served to establish bovine herpesvirus 1 (BHV-1) as the prototype member of ruminant herpesviruses. Based on the genomic sequence of the virus, we aim to identify and characterize virus-specified components, to explain their concerted action, and to predict how the chain of events during the lytic and latent phases of the viral life cycle may be interrupted. The nucleotide sequence of the BHV-1 genome (136 kb) has just been completed by international cooperation (July 1995; except for a small gap in UL36). It comprises 67 unique genes and 2 genes, both duplicated, in the inverted repeats. In general, these genes exhibit strong homology at the amino acid sequence level to those of other alphaherpesviruses (HSV-1, VZV, EHV-1) and are arranged in similar order. A few genes are peculiar to only one or two herpesviruses, e.g. in BHV-1 the circ, UL0.5, UL3.5 and US1.5 genes. Not long ago, the repertoire of BHV-1 proteins under study was restricted to the three major glycoproteins (gB, gC, and gD) and thymidine kinase. The repertoire is now growing rapidly and includes 7 additional glycoproteins (gE, gI, gH, gL, gG, gK and gM), a number of enzymes (e.g. ribonucleotide reductase, DNA Polymerase, dUTPase), and a group of regulatory proteins (BICPO, 4, 22, and 27, alpha TIF). Investigations into the functions of these proteins and comparison with their counterparts in other herpesviruses should reveal which are useful targets for diagnosis, prevention or antiviral treatment. Recombinant viruses containing deletions or replacements of individual genes are being created, aiming at vaccine development and insights into pathogenesis, notably latency, neurotropism, and interference with host functions. Molecular analysis of other ruminant herpesviruses is much less advanced. Over a dozen virus species have been described; most share basic properties with BHV-1 and may be classified as alphaherpesviruses. The gammaherpesviruses are represented by the proposed agent of malignant catarrhal fever, alcelaphine herpesvirus 1, and by bovine herpesvirus 4, whose partial sequences exhibit similarity to herpesvirus saimiri.
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PMID:Molecular virology of ruminant herpesviruses. 901 Sep 95

We report the nucleotide sequence of a 31-kb segment at the left genome end of bovine herpesvirus-1 (BHV-1) and show that it comprises 19 different open reading frames (ORFs), including seven which have been described previously (circ, dUTPase, UL49.5, alpha TIF, VP8, glycoprotein C, and ribonucleotide reductase small subunit). The new sequence resulted in a correction at the C-terminus of glycoprotein C. All 19 ORFs exhibited strong amino acid sequence homology to the gene products of other alphaherpesviruses. The BHV-1 ORFs were arranged colinearly with the prototype sequence of herpes simplex virus 1 (HSV-1) in the range of the UL54 to UL37 genes. No BHV-1 homologs of the HSV-1 UL56, UL55, and UL45 genes were identified. The BHV-1 circ gene was the only gene without a HSV-1 counterpart. The additional ORFs 1 and 2 found at the left genome end of equine herpesvirus-1 (EHV-1) were absent in BHV-1. Among the newly sequenced BHV-1 ORFs are homologs of ICP27 (UL54), glycoprotein K (UL53), helicase-primase (UL52), DNA polymerase accessory protein (UL42), ribonucleotide reductase large subunit (UL39), and several virion proteins (UL49, UL46, UL43, UL41, UL38, UL37), most of which are strongly conserved in all herpesviruses. The possible functions of the proteins encoded within the sequenced region are assessed and features found are discussed.
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PMID:Gene contents in a 31-kb segment at the left genome end of bovine herpesvirus-1. 901 Sep 99

Detection of genomic differences predictive of drug response or resistance in individual patients may allow therapy to be customized to the characteristics of particular tumors. Preliminary findings are that non-small cell lung cancer patients overexpressing ERCC1 mRNA have lower response to cisplatin chemotherapy, while those overexpressing ribonucleotide reductase mRNA have limited benefit from gemcitabine. In addition, overexpression of beta-tubulin III and stathmin can influence the sensitivity to microtubule interacting drugs, like vinorelbine and paclitaxel. The introduction of biological agents which target highly specific intracellular pathways offers the promise of enhancing the efficacy of cytotoxic chemotherapy. Among many promising biological agents is the monoclonal antibody C225, which blocks the EGFR receptor. The addition of C225 appears to induce responses in a proportion of colon cancer patients refractory to 5-FU or irinotecan, supporting pre-clinical evidence of synergistic activity. It also appears from xenograft data that C225 enhances the sensitivity of tumors to radiation and docetaxel or the combination.
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PMID:Molecular markers and targeted therapy with novel agents: prospects in the treatment of non-small cell lung cancer. 1248 Jan 94

Mechanisms of acquired resistance to three purine analogues, 2-chloro-2'-deoxyadenosine (cladribine, CdA), 9-beta-D-arabinofuranosyl-2-fluoroadenine (fludarabine, Fara-A), and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (clofarabine, CAFdA) were investigated in a human T-lymphoblastic leukemia cell line (CCRF-CEM). These analogues are pro-drugs and must be activated by deoxycytidine kinase (dCK). The CdA and CAFdA resistant cell lines exhibited increased resistance to the other nucleoside analogues activated by dCK. This was also the case for the Fara-A resistant cells, except that they were sensitive to CAFdA and guanosine analogues. The CdA and CAFdA resistant cells displayed a deficiency in dCK activity (to <5%) while the Fara-A resistant cells showed only a minor reduction of dCK activity (20% reduction). The activity of high K(m) 5'-nucleotidase (5'-NT) (cN-II) using IMP as substrate, was 2-fold elevated in the resistant cell lines. The amount of the small subunit R2 of ribonucleotide reductase (RR) was higher in the Fara-A resistant cells, which translated into a higher RR activity, while CdA and CAFdA cells had decreased activity compared to the parental cells. Expression of the recently identified RR subunit, p53R2 full-size protein, in CAFdA cells was low compared to parental cells, but a protein of lower molecular weight was detected in CdA and CAFdA cells. Co-incubation of Fara-A with the RR inhibitor 3,4-dihydroxybenzohydroxamic acid (didox) enhanced cytotoxicity in the Fara-A resistant cells by a factors of 20. Exposure of the cells to the nucleoside analogues studied here also caused structural and numerical instability of the chromosomes; the most profound changes were recorded for CAFdA cells, as demonstrated by SKY and CGH analysis. We conclude that down-regulation of dCK in cells resistant to CdA and CAFdA and increased activity of RR in cells resistant to Fara-A contribute to resistance.
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PMID:Down-regulation of deoxycytidine kinase in human leukemic cell lines resistant to cladribine and clofarabine and increased ribonucleotide reductase activity contributes to fludarabine resistance. 1250 99

Herpes simplex viruses types 1 (HSV-1) and 2 (HSV-2) are associated with a wide range of diseases related to infection of epithelial or neuronal tissues. The two viruses evidence distinct pathogenesis aspects, which are likely mediated by distinct viral genes. One such gene is UL39, which codes for the large subunit of ribonucleotide reductase (R1, also known as ICP6 and ICP10 for HSV-1 and HSV-2 respectively). The HSV-2 R1 has serine-threonine protein kinase (PK) activity, which is located within the first 411 amino acids (ICP10PK). ICP10PK is a constitutively activated growth factor receptor (GFR) that signals through the Ras/MEK/ERK pathway. It has transforming activity in immortalized cells, mitogenic (but not transforming) activity in normal diploid cells, and anti-apoptotic (survival) activity in post mitotic neurons in the central nervous system (CNS). In addition to the Ras/MEK/ERK, ICP10PK also activates the PI3-K/Akt pathway, upregulates the Ras family member Rap-1 and adenylate cyclase and activates the B-Raf kinase activity. ICP10 PK appears to have a cellular origin. Its conservation is most likely to reflect the ability to impart an evolutionary advantage, particularly in the face of pro-apoptotic viral genes. Indeed, activation of the Ras/MEK/ERK pathway by ICP10PK is required for virus growth.
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PMID:The herpes simplex virus type 2 protein ICP10PK: a master of versatility. 1597 May 36

The mat2,3-region of Schizosaccharomyces pombe is flanked by two inverted repeat elements, IRL and IRR, which define the boundaries of the silent domain resulting from heterochromatin assembly in the region. We employed a genetic screen to isolate factors whose mutations allowed spreading of heterochromatin across boundary elements. Surprisingly, this screen revealed that mutations in the genes required for deoxyribonucleotide biosynthesis, cdc22 (encoding the large subunit of ribonucleotide reductase) and tds1 (putative thymidylate synthase), cause silencing of marker genes inserted outside of the silent domain. Chromatin-immunoprecipitation analysis showed that histone H3 lysine 9 methylation modification, an epigenetic mark associated with gene silencing, is enriched by two- to three-fold in the cdc22 mutant as compared to the level found in the wild-type strain in regions outside the silent domain. The spreading of heterochromatin across barriers required functional Atf1/Pcr1, ATF-CREB family proteins, but not the RNA-interference Dcr1, Ago1, or Rdp1 factors, previously implicated in silencing. These results implicate the deoxyribonucleotide biosynthesis pathway in limiting epigenetic controls at barrier elements at the mating-type region, but the mechanism remains unknown.
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PMID:Mutations in deoxyribonucleotide biosynthesis pathway cause spreading of silencing across heterochromatic barriers at the mating-type region of the fission yeast. 1803 Jun 66

Even with the introduction of targeted agents and the establishment of multiple lines of therapy, the median survival for patients with advanced non-small cell lung cancer (NSCLC) does not considerably extend beyond 1 year. Emerging research suggests that clinical characteristics alone are insufficient for selecting patients for therapies that may confer significant survival benefit. The discovery of predictive and prognostic molecular markers such as gene mutations in EGFR and KRAS as well as high tumor expression levels of DNA repair pathway components ribonucleotide reductase subunit 1 and excision repair cross-complementing group 1 has sparked an interest in the development of individualized therapy as a strategy for increasing survival in patients with NSCLC. Techniques to analyze molecular biomarkers, such as immunohistochemistry, fluorescence in situ hybridization, polymerase chain reaction, and, more recently, gene microarray techniques, are being investigated for their potential to accurately predict an individual patient's response to therapy. Many prospective trials are still needed to clarify and confirm the utility of molecular biomarkers for guiding treatment selection, and continued participation in clinical trials is critical for the development of tools to provide customized treatment plans for patients with NSCLC.
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PMID:Molecular analysis-based treatment strategies for the management of non-small cell lung cancer. 1970 47

Deregulation of the expression of p53R2, a p53-inducible homologue of the R2 subunit of ribonucleotide reductase, has been found in various human cancer tissues; however, the roles p53R2 plays in cancer progression and malignancy remain controversial. In the present study, we examined changes in gene expression profiles associated with p53R2 in cancer cells, using the analysis of cDNA microarray. Gene set enrichment analysis identified that the gene set regulating cell-cycle progression was significantly enriched in p53R2-silencing human oropharyngeal carcinoma KB cells. Attenuation of p53R2 expression significantly reduced p21 expression and moderately increased cyclin D1 expression in both wild-type p53 cancer cells (KB and MCF-7) and mutant p53 cancer cells (PC3 and MDA-MB-231). Conversely, overexpression of p53R2-GFP resulted in an increase in the expression of p21 and decrease in the expression of cyclin D1, which correlated with reduced cell population in S-phase in vitro and suppressed growth in vivo. Furthermore, the MAP/ERK kinase inhibitor PD98059 partially abolished modulation of p21 and cyclin D1 expression by p53R2. Moreover, under the conditions of nonstress and adriamycin-induced genotoxic stress, attenuation of p53R2 in KB cells significantly increased phosphorylated H2AX, which indicates that attenuation of p53R2 may enhance DNA damage induced by adriamycin. Overall, our study shows that p53R2 may suppress cancer cell proliferation partially by upregulation of p21 and downregulation of cyclin D1; p53R2 plays critical roles not only in DNA damage repair but also in proliferation of cancer cells.
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PMID:p53R2 inhibits the proliferation of human cancer cells in association with cell-cycle arrest. 2121 34

We report a rare presentation of a 66-year-old female with diffuse metastatic adenocarcinoma of unknown primary involving liver, lymphatic system and bone metastases. The neoplastic cells were positive for CK7 and OC125, while negative for CK20, thyroid transcription factor 1, CDX2, BRST-2, chromogranin, synaptophysin, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu). Fluorescence in situ hybridization showed no amplification of the HER2/neu gene. Molecular profiling reported a breast cancer origin with a very high confidence score of 98%. The absence of immunohistochemistry staining for ER, PR, and HER2/neu further classified her cancer as triple-negative breast cancer. Additional studies revealed high expression levels of topoisomerase (Topo) I, androgen receptor, and ribonucleoside-diphosphate reductase large subunit; the results were negative for thymidylate synthase, Topo II-a and O6-methylguanine-DNA methyltransferase. The patient was initially treated with a combination regimen of cisplatin and etoposide, and she experienced a rapid resolution of cancer-related symptoms. Unfortunately, her therapy was complicated by a cerebrovascular accident (CVA), which was thought to be related to cisplatin and high serum mucin. After recovery from the CVA, the patient was successfully treated with second-line chemotherapy based on her tumor expression profile. We highlight the role of molecular profiling in the diagnosis and management of this patient and the implication of personalized chemotherapy in this challenging disease.
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PMID:Occult breast cancer presenting as metastatic adenocarcinoma of unknown primary: clinical presentation, immunohistochemistry, and molecular analysis. 2237 71

The elucidation of the molecular alterations in non-small cell lung cancer (NSCLC) and the development of molecularly targeted agents have permanently shifted NSCLC therapy to a personalized approach. In the metastatic setting, the addition of the anti-vascular endothelial growth factor monoclonal antibody, bevacizumab, to chemotherapy improves overall survival. The oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, prolong progression-free survival in patients selected for the presence of an EGFR activating mutation. The monoclonal antibody to EGFR, cetuximab, improves survival in patients with metastatic NSCLC, and the inhibitor of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein, crizotinib, has resulted in an unprecedented overall survival advantage in patients harboring the EML4-ALK translocation. In the adjuvant setting, gefitinib has not been shown to improve patient survival outcomes; however, there are several ongoing clinical trials in the adjuvant setting evaluating the role of erlotinib, bevacizumab, and the MAGE-A3 and MUC1 vaccines. The realm of personalized lung cancer therapy also includes the study of chemotherapy selected on the basis of the pharmacogenetic profile of a patient's tumor. Several ongoing clinical trials in both the metastatic and adjuvant settings are studying the excision repair cross-complementing group 1 (ERCC1) protein, the ribonucleotide reductase subunit 1 (RRM1) protein, thymidylate synthase, and BRCA1 as predictors of chemotherapy response. This review will outline the current state of the art of personalized NSCLC therapy.
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PMID:Personalized therapy for non-small cell lung cancer: which drug for which patient? 2244 47


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