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)

Transcripts coding for transcription factors (RB, P53, FOS, MYC, MYB, ERBA, REL), growth factors (FGF1, FGF2, INT2, TGFA, TGFB, PDGF, IGF1, IGF2), interleukins, (IL1, IL2, IL3, IL4, IL6, TNF), growth-factor receptors or cytosolic protein kinases (RAF, PIM, FES, MET, SRC, ROS, TRK, KIT, CSFR, IGFR, PDGFR, EGFR, NEU) were quantified in cultured human mammary fibroblasts from normal tissues, benign tumours, carcinomas and post-radiation fibrosis lesions by slot-blot autoradiography and image analysis. The effects of a differentiating agent (cholera toxin) and of a tumour promoter (12-O-tetradecanoyl-phorbol-13-acetate) were also examined. The drugs modulated the levels of the anti-oncogene transcripts (RB, P53) and of ERBA, REL, RAF, MET, ROS, TRK, CSFR, EGFR, NEU, FGF1, INT2, IGF1, IL1, IL2, IL4 and IL6. Apart from this variation, there were multiple differences in gene expression among normal and pathological cells (concerning all but P53, TGFB and interleukin transcripts) and between sub-types defined by the presence of alpha-sm-actin (myofibroblasts) or EDB-fibronectin (RAF, ROS, FES, KIT, IGFR, NEU, INT2, TGFB, PDGF, IGFs, ILs). It appears, therefore, that mammary stroma progress irreversibly along with the epithelium during tumoral development, and that breast cancer is not only a multi-gene but also a multi-tissue phenotype.
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PMID:Quantitative variation of proto-oncogene and cytokine gene expression in isolated breast fibroblasts. 776 44

Aberrant function of protein kinases has been implicated in the development of melanoma. In an effort to define the molecular events involved in initiation and progression of this malignancy, we used RT-PCR to identify protein kinases in both normal and transformed melanocytes. Collectively, we identified seven clones corresponding to previously characterized protein kinases (JAK-1, TYK02, AXL/UFO, IGF1-R, KDR and FER) as well as the recently identified MLK-3/PTK1 protein kinase. Northern analysis was used to determine the expression pattern of each protein kinase in both normal melanocytes and a variety of melanoma cell lines. Relatively abundant levels of UFO/AXL and KDR mRNAs were observed in a subset of the melanoma cell lines whereas most of the remaining protein kinases were expressed at similar levels in both normal and transformed melanocytes.
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PMID:Protein kinases in normal and transformed melanocytes. 785 16

We have used the polymerase chain reaction and Northern blotting to identify protein tyrosine kinases that may play an important role in the process of melanoma initiation and progression. Degenerate primers from the conserved catalytic domain of tyrosine kinase genes were used to amplify and clone partial cDNA sequences from a human melanoma cell line (DX3-LT5.1) and normal human melanocytes. When the melanoma reaction products were sequenced, 13 distinct clones were found, of which one is novel to date and has provisionally been named MEK (for melanocytic kinase). Of the remaining 12 known kinases, only two, ERB-B2 and IGF1-R, have previously been reported in pigment cells. Reaction products from melanocytes included only eight of these 13 sequences. To test for quantitative differences in tyrosine kinase expression between normal and malignant cells, a panel of eight melanoma lines and normal melanocytes was analyzed by Northern blotting. Two tyrosine kinases (JTK-14/TIE and TYRO-9) were detected in some melanomas but were not found in normal melanocytes, whereas others, including MEK, appeared to be overexpressed in some malignant lines. A minority of kinases showed either no change or a reduction in the level of mRNA. Expression of tyrosine kinases varied independently, and individual lines contained various combinations of these enzymes. Our findings are consistent with an increased overall expression of these putative growth factor receptors during melanoma development.
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PMID:Novel and known protein tyrosine kinases and their abnormal expression in human melanoma. 822 28

Insulin, insulin-like growth factor-I (Igf-I), and insulin-like growth factor-II (Igf-II) are known to enhance growth in mouse preimplantation embryos. The addition of insulin, Igf-I, and Igf-II to mouse embryos in culture results in an increase in protein synthesis, cell number, and the proportion of embryos developing to the blastocyst stage. To study the role of the insulin-like growth factors in early human development, the timing of gene expression of insulin, IGF1, IGF2, and their receptors was analysed. Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the presence of transcripts in preimplantation embryos. Following reverse transcription, strategically designed nested primers were used for amplification from cDNA. Transcripts for all three receptors (insulin receptor, IGF1R, IGF2R) were present in human oocytes and preimplantation embryos. However, of the ligands, only IGF2 transcripts were detected. This is consistent with expressed patterns seen in the mouse. As in the human, mouse Igf2 is the only ligand in the family expressed and has been shown to have an autocrine effect on preimplantation development. It has previously been shown that insulin and Igf-I are produced by the mouse maternal reproductive tract and have a paracrine effect on the preimplantation embryo. We speculate that a similar relationship exists in the human and that preimplantation development may be regulated by IGFs from both embryonic (IGF-II) and maternal (insulin and IGF-I) sources.
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PMID:Expression of mRNA for the insulin-like growth factors and their receptors in human preimplantation embryos. 913 13

Degenerate polymerase chain reaction against conserved kinase catalytic subdomains identified 15 tyrosine and serine-threonine kinases expressed in surgically removed prostatic carcinoma tissues, including six receptor kinases (PDGFBR, IGF1-R, VEGFR2, MET, RYK, and EPH-A1), six non-receptor kinases (ABL, JAK1, JAK2, TYK2, PLK-1, and EMK), and three novel kinases. Several of these kinases are oncogenic, and may function in the development of prostate cancer. One of the novel kinases is a new member of the sterile 20 (STE20) family of serine-threonine kinases which we have called prostate-derived STE20-like kinase (PSK) and characterized functionally. PSK encodes an open reading frame of 3705 nucleotides and contains an N-terminal kinase domain. Immunoprecipitated PSK phosphorylates myelin basic protein and transfected PSK stimulates MKK4 and MKK7 and activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway. Microinjection of PSK into cells results in localization of PSK to a vesicular compartment and causes a marked reduction in actin stress fibers. In contrast, C-terminally truncated PSK (1-349) did not localize to this compartment or induce a decrease in stress fibers demonstrating a requirement for the C terminus. Kinase-defective PSK (K57A) was unable to reduce stress fibers. PSK is the first member of the STE20 family lacking a Cdc42/Rac binding domain that has been shown to regulate both the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and the actin cytoskeleton.
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PMID:PSK, a novel STE20-like kinase derived from prostatic carcinoma that activates the c-Jun N-terminal kinase mitogen-activated protein kinase pathway and regulates actin cytoskeletal organization. 1066 Jun

Previous reports have demonstrated that expression of insulin-like growth factor 2 (IGF2) is altered in hepatoblastoma. Using RNAase protection analysis (RPA), we examined the gene expression for IGF1, IGF2, IGF1R, M6P/IGF2R, IGFBP-1 and IGFBP-2 in a series of hepatoblastomas with corresponding normal liver from the same individuals. The results show that the expression of the IGF-axis members included in the present study are altered between tumour and normal, and indicate that the IGF-axis may be involved in hepatoblastoma development.
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PMID:Altered expression of members of the IGF-axis in hepatoblastomas. 1078 25

Congenital fibrosarcoma (CFS) and cellular mesoblastic nephroma (CMN) are pediatric spindle cell malignancies that share two specific cytogenetic abnormalities: trisomy of chromosome 11 and a t(12;15)(p13;q25) translocation. The t(12;15) rearrangement creates a transcriptionally active fusion gene that encodes a chimeric oncoprotein, ETV6-NTRK3 (EN). EN transforms NIH3T3 fibroblasts through constitutive activation of both the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3'kinase (PI3K)-Akt pathway. However, the role of trisomy 11 in CFS and CMN remains unknown. In this study we demonstrate elevated expression of the chromosome 11p15.5 insulin-like growth factor 2 gene (IGF2) in CFS and CMN tumors. Moreover, we present evidence that an intact IGF signaling axis is essential for in vitro EN-mediated transformation. EN only very weakly transformed so-called R-murine fibroblasts derived from mice with a targeted disruption of the IGF1 receptor gene (IGFRI), but transformation activity was fully restored in R- cells engineered to re-express IGFRI (R+ cells). We also observed that the major IGFRI substrate, insulin-receptor substrate-1 (IRS-1), was constitutively tyrosine phosphorylated and could be co-immunoprecipitated with EN in either R- or R+ cells expressing the EN oncoprotein. IRS-1 association with Grb2 and PI3K p85, which link IGFRI to the Ras-MAPK and PI3K-Akt pathways, respectively, was enhanced in both cell types in the presence of EN. However, activation of the Ras-MAPK and PI3K-Akt pathways was markedly attenuated in EN-expressing R- cells compared to EN-transformed R+ cells. This suggests that IRS-1 may be functioning as an adaptor in EN signal transduction, but that a link to EN transformation pathways requires the presence of IGFRI. Our findings indicate that an intact IGF signaling axis is essential for EN transformation, and are consistent with a role for trisomy 11 in augmenting this pathway in EN expressing tumors.
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PMID:ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation. 1217 38

Recent studies have demonstrated a significant association between mutations in genes involved in the insulin/IGF1 signaling pathway and extension of the life span of model organisms. In this study which compared 122 Japanese semisupercentenarians (older than 105) with 122 healthy younger controls, we examined polymorphic variations of six genes which are involved in insulin/IGF1 signaling. These genes were FOXO1A, INSR, IRS1, PIK3CB, PIK3CG, and PPARGC1A. We investigated the possible association of each gene locus and longevity by haplotype-based association analyses using 18 SNPs from public databases and the published literature. One INSR haplotype, which was comprised of 2 SNPs in linkage disequilibrium, was more frequent in semisupercentenarians than in younger controls.
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PMID:Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways. 1558 74

Growth hormone (GH), insulin-like growth factors 1 and 2 (IGF1 and IGF2) and their associated binding proteins and transmembrane receptors (GHR, IGF1R and IGF2R) play an important role in the physiology of mammalian growth. The objectives of the present study were to estimate the allele and genotype frequencies of microsatellite markers located in the 5'-regulatory region of the IGF1 and GHR genes in beef cattle belonging to different genetic groups and to determine effects of these markers on growth and carcass traits in these animals under an intensive production system. For this purpose, genotyping was performed on 384 bulls including 79 Nellore, 30 Canchim (5/8 Charolais + 3/8 Zebu) and 275 crossbred animals originating from crosses of Simmental (1/2 Simmental, n = 30) and Angus (1/2 Angus, n = 245) sires with Nellore females. The effects of substituting L allele for S allele of GHR microsatellite across Nellore, Canchim and 1/2 Angus were significant for weight gain and body weight (P < 0.05). The IGF1 microsatellite allele substitutions of 229 for 225 within Nellore group and of 225 for 229 within 1/2 Angus were not significant for any of the traits.
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PMID:Effects of polymorphic microsatellites in the regulatory region of IGF1 and GHR on growth and carcass traits in beef cattle. 1567 Jan 32

We have developed two bioluminescence resonance energy transfer (BRET)-based approaches to monitor 1) ligand-induced conformational changes within partially purified insulin-like growth factor-1 (IGF-1) receptors (IGF1R) and 2) IGF1R interaction with a substrate-trapping mutant of protein tyrosine phosphatase 1B (PTP1B-D181A) in living cells. In the first assay, human IGF1R fused to Renilla reniformis luciferase (Rluc) or yellow fluorescent protein (YFP) were cotransfected in human embryonic kidney (HEK)-293 cells. The chimeric receptors were then partially purified by wheat germ lectin chromatography, and BRET measurements were performed in vitro. In the second assay, BRET measurements were performed on living HEK-293 cells cotransfected with IGF1R-Rluc and YFP-PTP1B-D181A. Ligand-induced conformational changes within the IGF1R and interaction of the IGF1R with PTP1B could be detected as an energy transfer between Rluc and YFP. Dose-response experiments with IGF-1, IGF-2, and insulin demonstrated that the effects of these ligands on BRET correlate well with their known pharmacological properties toward the IGF1R. Inhibition of IGF1R autophosphorylation by the tyrphostin AG1024 (3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile) resulted in the inhibition of IGF1-induced BRET signal between the IGF1R and PTP1B. In addition, an anti-IGF1R antibody known to inhibit the biological effects of IGF-1 inhibited ligand-induced BRET signal within the IGF1R, as well as between IGF1R and PTP1B. This inhibition of BRET signal paralleled the inhibition of the ligand-induced autophosphorylation of the IGF1R by this antibody. In conclusion, these BRET-based assays permit 1) the rapid evaluation of the effects of agonists or inhibitory molecules on IGF1R activation and 2) the analysis of the regulation of IGF1R-PTP1B interaction in living cells.
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PMID:Monitoring the activation state of the insulin-like growth factor-1 receptor and its interaction with protein tyrosine phosphatase 1B using bioluminescence resonance energy transfer. 1597 35


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