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)

The epithelium to mesenchyme transition is thought to play a fundamental role during embryonic development and tumor progression. Loss of cell-cell adhesion and modification of both cell morphology and gene expression are the main events associated with this transition. There is a large amount of evidence suggesting that growth factors can initiate these events. Yet, the connection from growth factor induction to changes in cell adhesion and morphology is largely unknown. To elucidate this connection, we have investigated the action of IGF-II on E-cadherin/beta-catenin complex-mediated cell-cell adhesion and on beta-catenin/TCF-3 mediated gene expression. We can show that (1) IGF-II induces a rapid epithelium to mesenchymal transition; (2) IGF1R, the receptor for IGF-II, belongs to the same membrane complex as E-cadherin and beta-catenin; (3) IGF-II induces a redistribution of beta-catenin from the plasma membrane to the nucleus and an intracellular sequestration and degradation of E-cadherin; (4) IGF-II induces the transcription of beta-catenin/TCF-3 target genes. Based on the given case of IGF-II and E-cadherin/beta-catenin complex, this study reveals the backbone of a cascade connecting growth factor signaling with cell-cell adhesion during EMT.
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PMID:IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition. 1152 79

A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzenes possessing a 5-I or 5-CF3 substituent, that were originally designed as thymidine mimics, were coupled via their 5'-OH group to a cyclosaligenyl (cycloSal) ring system having a variety of C-3 substituents (Me, OMe, H). The 5'-O-cycloSal-pronucleotide concept was designed to effect a thymidine kinase-bypass, thereby providing a method for the intracellular delivery and generation of the 5'-O-monophosphate for nucleosides that are poorly phosphorylated. The 5'-O-cycloSal pronucleotide phosphotriesters synthesized in this study were obtained as a 1:1 mixture of two diastereomers that differ in configuration (S(P) or R(P)) at the asymmetric phosphorous center. The (S(P))- and (R(P))-diastereomers for the 5'-O-3-methylcycloSal- and 5'-O-3-methoxycycloSal derivatives of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene were separated by silica gel flash column chromatography. This class of cycloSal pronucleotide compounds generally exhibited weak cytotoxic activities in a MTT assay (CC50 values in the 10(-3) to 10(-4) M range), against a number of cancer cell lines (143B, 143B-LTK, EMT-6, Hela, 293), except for cyclosaligenyl-5'-O-[1'-(2,4-difluoro-5-iodophenyl)-2'-deoxy-beta-D-ribofuranosyl]phosphate that was more potent (CC50 values in the 10(-5) to 10(-6) M range), than the reference drug 5-iodo-2'-deoxyuridine (IUDR) which showed CC50 values in the 10(-3) to 10(-5) M range.
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PMID:Cyclosaligenyl pronucleotides of 5-iodo and 5-trifluoromethyl-1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzene mimics of thymidine: synthesis and evaluation of this pronucleotide monophosphate delivery system for compounds with potential anticancer activity. 1471 61

A group of 3'-O- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines possessing a variety of substituents (H, Me, I, F, CF(3)) at the C-5 position of the nucleoside moiety were synthesized for evaluation as hybrid anticancer agents that have the ability to simultaneously release cytotoxic nitric oxide (*NO). Incubation of these nitric oxide donor-nucleoside conjugates in the presence of 18 mM L-cysteine released a high percentage of *NO (21-48% at 1 h; 37-86% at 16 h). The release of *NO in the absence of the thiol cofactor was negligible. These hybrid *NO donor-nucleosides exhibited high cellular toxicity (CC(50) = 10(-6)-10(-8) M range) against a battery of tumor cell lines (143B-LTK, 143B, EMT-6, KBALB-STK, and KBALB) and normal human fibroblasts (Hs578Bst). No differences in cytotoxicity between nontransfected (143B, KBALB) and the corresponding transfected (143B-LTK, KBALB-STK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK(+)) were observed, indicating that expression of the viral TK enzyme did not provide a gene therapeutic effect.
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PMID:Design and synthesis of 3'- and 5'-O-(3-benzenesulfonylfuroxan-4-yl)-2'-deoxyuridines: biological evaluation as hybrid nitric oxide donor-nucleoside anticancer agents. 1502 76

Pre-eclampsia is one of the most common causes of perinatal and maternal morbidity and mortality. High blood pressure and proteinuria are important clinical signs of pre-eclampsia. Sympathetic overactivity and elevated level of circulating vaso active substances, such as monoamines has been shown. Extracellular concentrations of monoamines are normally kept low by specific transporter proteins of which many are expressed in the placenta. In this study we used in situ hybridization and real-time PCR to study the gene expression of monoamine transporters, such as NET, SERT, VMAT2, EMT and OCT1/2, in normal as well as in pre-eclamptic placentae. We demonstrated high expression of NET mRNA in the trophoblast cells of the anchoring villi and a lower expression intensity in the chorionic villi. SERT mRNA was mainly detected in chorionic villi. VMAT2 mRNA was not detected in the central part of the placenta but was present in the spiral arteries of placenta bed biopsies, in cytokeratin positive cells. EMT mRNA was mainly detected in the intra lobular septa and together with OCT1 and OCT2 mRNAs also expressed in scattered cells of placental vessel adventitias. Moreover, quantitative analysis showed a significant lower expression of NET and EMT mRNAs in pre-eclamptic placentae as compared to the control group. A defective gene expression or function of these monoamines transporters might explain the elevated concentrations of monoamines in pre-eclamptic patients. Monoamine transporters may serve as a protective mechanism preventing vasoconstriction in the placental vascular bed and thereby securing a stable blood flow to the fetus.
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PMID:Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. 1513 35

In vivo transfer of the herpes simplex virus type-1 thymidine kinase (HSV-1 TK) gene, with subsequent administration of antiviral drugs such as ganciclovir, has emerged as a promising gene therapy protocol for treating proliferative disorders. The in vitro cytotoxicities (IC(50)) for two series of 5-iodo- and (E)-5-(2-iodovinyl)-substituted 2'-deoxy- and 2'-deoxy-2'-fluoro-pyrimidine nucleosides ranged from millimolar to low nanomolar concentrations in mammalian tumor cell lines (KBALB; R-970-5; 143B; EMT-6) and their counterparts engineered to express HSV-1 TK (KBALB-STK; 143B-LTK). Their HSV-1 TK selectivity indices ranged from one (nonselective) to one million (highly selective) based on cytotoxicity, with FIRU being the least toxic to all cell lines, and FIAU being most toxic. HSV-1 TK selectivity, based on uptake, ranged from 10 to 140, with IVDU being most selective for HSV-1 TK expressing cells, followed by IVFRU, FIRU, FIAU, IVFAU and finally IUDR. Phosphorylation of [(125)I]FIAU led to incorporation of the radiolabel into nucleic acids, whereas IVFRU and FIRU radioactivity was trapped primarily in the nucleotide pool. These data indicate that cytotoxicity does not depend on initial metabolic trapping (e.g., phosphorylation), but on elaboration of the mononucleotides to more cytotoxic anabolites. Lipophilicities and nucleoside transport rates of the six nucleosides tested were within narrow ranges. This supports the premise that cellular biochemistry, and not cellular bioavailability, is responsible for the observed broad range of cytotoxicity and trapping. In vivo biodistribution studies with 5-[(125)I]iodo-2'-fluoro-2'-deoxyribouridine (FIRU), 5-[(125)I]iodo-2'-fluoro-2'-deoxyarabinouridine (FIAU) and (E)-5-(2-[(125)I]iodovinyl)-2'-fluoro-2'-deoxyuridine (IVFRU) demonstrate selective accumulation of all three radiotracers in HSV-1 TK-expressing KBABK-STK tumors, compared to their very low accumulation in the non-HSV-1 TK-expressing KBALB tumors, in Balb/c mice. In summary, these nucleosides are unpredictably cytotoxic to the various cell lines studied, and this unpredictability extends across the HSV-1 TK expression characteristic; their uptake by cells engineered to express HSV-1 TK is also dependent on the molecular construction of the gene cassette carrying the viral TK gene.
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PMID:Cytotoxicity and cellular uptake of pyrimidine nucleosides for imaging herpes simplex type-1 thymidine kinase (HSV-1 TK) expression in mammalian cells. 1521 81

Embryonal stem (ES) cells are the earliest ontogenetically identifiable stem cells of the embryo proper for all subsequent mesenchymal stem cells and for highly specialized differentiated cells. This review characterizes, in a working hypothesis, the role of reversible EMT/MET (epithelialmesenchymal transition) as a manifestation of cell plasticity 1) in the development of ES cells to adult stem cells (hematopoietic stem cells) and 2) in metastasizing cancer cells. Animal studies support the concept that EMT/MET is a key manifestation of cell plasticity in the development of ES cells to adult stem cells, and in conversion of localized to metastasizing cancer cells. In fact, ES cells may persist to postnatal life, in cytologically verifiable form and/or within the frame of EMT/MET, as ultimate reservoir for adult stem cells. Furthermore, EMT could possibly serve as a conceptional link between physiologic and pathologic signaling pathways. Clonal confirmation in humans is necessary.
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PMID:Hypothesis: cell plasticity, linking embryonal stem cells to adult stem cell reservoirs and metastatic cancer cells? 1596 49

Twist, a newly found EMT-inducer, has been reported to be up-regulated in those of diffuse-type gastric carcinomas with high N-cadherin level. We show here MKN45, a cell line derived from undifferentiated carcinomas cells, expresses high levels of Twist. Down-regulation of Twist, using an antisense Twist vector in MKN45 cells, inhibits cell migration and invasion, companied with a morphologic changes associated with MET. Suppression of Twist also decreases the expressions of N-cadherin and fibronectin, but not of E-cadherin in MKN45. In contrast, overexpression of Twist in MKN28, a cell line derived from moderate differentiated carcinomas, results in up-regulation of N-cadherin and fibronectin, companied with down-regulation of E-cadherin. Taken together, our results suggest that Twist regulates cell motility and invasion in gastric cancer cell lines, probably through the N-cadherin and fibronectin production.
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PMID:Up-regulation of gastric cancer cell invasion by Twist is accompanied by N-cadherin and fibronectin expression. 1751 4

Hepatocellular carcinoma (HCC) is a frequent neoplasia which still misses a therapeutical gold standard. Recently, new acquisitions in cancerogenesis process evidenced the genetic and epigenetic alterations of genes involved in the different metabolic pathways of liver cancer suggesting that antibodies, small molecules, demethylating agents, etc. specifically acting against molecular target can be utilized alone or in combination in clinical practice. The main altered targets are: cell membrane receptors, in particular tyrosine kinase receptors, factors involved in cell signalling, specifically Wnt/beta-catenin, Ras/Raf/MEK/ERK and PI3K/Akt/mTOR pathways, proteins linked to cell cycle regulation pathway (i.e. p53, p16/INK4, cyclin/cdk complex) or in invasiveness (EMT, TGFbeta) and proteins involved in DNA metabolism. Genetic or epigenetic changes in these molecules have been used in preclinical settings and, some of them also in clinical trials of phase II and III. This scenario opens new avenues for the prevention and the treatment of HCC. In the present review the main metabolic pathways and molecular alterations have been described together with recent advances in molecular and gene therapy.
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PMID:Molecular pathways and related target therapies in liver carcinoma. 1804 79

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent manner. Sensitive cell lines also exhibited increased expression of EGFR ligands or HER3. In contrast, lapatinib-resistant cell lines exhibited high androgen receptor (AR) levels or epithelial-to-mesenchymal transition (post-EMT) features. In endometrial cancer cells, at a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for lapatinib plus carboplatin, paclitaxel, docetaxel, and doxorubicin. These observations provide a clear biologic rational to test lapatinib as a single agent or in combination with chemotherapy in endometrial cancer with HER2 overexpression. Expression of EGFR, its ligands, HER3, AR, and post-EMT markers warrant further evaluation to help define patients with HER2-nonoverexpressing endometrial cancer most likely to benefit from lapatinib.
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PMID:Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells. 1833 72

The constitutive activation of beta-catenin-dependent ('canonical') Wnt signalling is a necessary initiating event in the genesis of most colorectal cancers. As this constitutive activation occurs through genetic mutation of one of the down-stream components of the signalling pathway, it was presumed that additional regulation of beta-catenin-dependent Wnt signalling would be inconsequential. However, it is now recognised that additional modulation of beta-catenin-dependent Wnt signalling is involved in tumour progression, and many of the genes associated with tumour invasion and metastasis are beta-catenin/TCF transcriptional target genes that are dynamically regulated during cancer progression. Intriguingly, the demonstration that naturally occurring inhibitors of Wnt-Frizzled (FZD) interaction are bona fide tumour suppressors in this cancer suggests that additional modulation of Wnt signalling is via the upstream components of the pathway. This is corroborated by recent studies that demonstrate tumour-promoting roles for Wnt and FZD per se. Moreover, both beta-catenin-dependent and beta-catenin-independent Wnt/FZD-mediated signalling is implicated during the dynamic and reversible EMT and MET that underscore colorectal cancer progression. Importantly, therapeutic targeting of the Wnt signalling pathway at the plasma membrane is clearly indicated by the profound anti-tumour activity of small molecule inhibitors and dominant-negative receptor constructs that target the receptor complex. The potential to effectively target EMT and MET processes at the plasma membrane via the upstream components of the Wnt signalling pathway offers new hope for anti-cancer therapy.
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PMID:The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. 1835 Feb 53


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