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)

We have analyzed 95 blood- and 25 paraffin-derived DNA samples of 120 individuals from Switzerland (MEN 2 family members and patients with medullary thyroid carcinoma or pheochromocytoma) for the presence of RET protooncogene mutations in exons 10, 11, 13, 14 and 16, where recently germline point mutations have been identified in more than 95% of patients with MEN 2A, familial medullary thyroid carcinoma (FMTC) and MEN 2B. Molecular DNA screening of samples was performed by non-radioactive single strand conformation polymorphism (SSCP) and heteroduplex gel electrophoresis method followed by mutation analysis of PCR products by direct cycle sequencing using an automated DNA sequencer. We identified 12 MEN 2A/FMSC and 6 MEN 2B families with 29 gene carriers. Ten different types of mutations were identified in the MEN 2A/FMTC families (620 Cys-->Arg, 618 Cys-->Ser, Gly, 611 Cys-->Tyr; 634 Cys-->Arg, Tyr, Trp, Phe, Ser, Gly) and all 6 MEN 2B families had a 918 Met-->Thr point mutation. Our results indicate that PCR-based DNA testing for RET point mutations is a rapid, accurate and reproducible method of identifying MEN 2 gene carriers using blood or tissue DNA. Early detection of gene carriers allows preventive thyroidectomy without neck dissection or parathyroid transplantation, and non-gene carriers can be released from biochemical testing. Furthermore, it is shown that the distribution and localization of RET mutations in MEN 2 families from Switzerland concur with combined results of larger series and that a "founder effect" of MEN 2 can be excluded for this country.
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PMID:[Detection of RET-proto-oncogene mutations in the diagnosis of Type 2 endocrine neoplasia (MEN 2)]. 876 74

To assess the feasibility of screening for multiple endocrine neoplasia type 2A (MEN 2A), the authors used DNA sequence analysis to evaluate the RET proto-oncogene in a kindred with MEN 2A. The kindred consisted of 95 members (1 to 79 years of age) and their spouses, and spanned five generations. Genomic DNA was extracted from peripheral blood lymphocytes or lymphoblastoid cell lines established from the family members, and the RET gene was amplified by polymerase chain reaction (PCR) using RET-specific primers (10q 11.2) and was sequenced. Periodic endocrine screening also was performed, by measuring the plasma calcitonin concentration after provocation with pentagastrin (0.5 microgram/kg intravenously) to assess its reliability for detecting the associated neoplasms. Nineteen patients were confirmed to have MEN 2A by medical records or the screening program. The DNA sequence of the PCR products from clinically established MEN 2A patients showed a mutation at codon 634 (TGC-->CGC) that resulted in an amino acid change from cysteine to arginine. Endocrine screening tests showed that six other family members had a mutated RET protooncogene. DNA sequencing can detect high-risk cases at a preclinical stage of the disease. The establishment of mutated MEN 2A gene carriers allows pediatric surgeons to consider total thyroidectomy at a very early stage of neoplasm development (C-cell hyperplasia) or even prophylactically.
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PMID:Germline mutations of the RET proto-oncogene in pedigree with MEN type 2A: DNA analysis and its implications for pediatric surgery. 878 1

The causative relationship between several of the syndromic forms of craniosynostosis and mutations in the fibroblast growth factor receptor (FGFR) loci is now well established. However, within the group of patients with craniosynostosis, there are several families and sporadic cases whose clinical features differ in variable degrees from the classically described syndromes of craniosynostosis. In this communication we present novel FGFR2 mutations associated with a spectrum of craniosyostosis phenotypes in 4 sporadic cases and in one family in which craniosynostosis segregates. The mutation and phenotype data presented emphasise the clinical variability of mutations at this locus and underline the plasticity of the phenotype-genotype relationship in this important group of congenital malformation syndromes. Mutations found were tyrosine 105 to cysteine, glycine 338 to glutamic acid, serine 351 to cysteine and glycine 384 to arginine. These are the first reported mutations in the first immunoglobulin-like loop (tyrosine 105 to cysteine) and the transmembrane domain (glycine 384 to arginine) of FGFR2, providing further insights into the mechanism of abnormal receptor function in FGFR2 mutations.
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PMID:Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus. 894 74

The HIV-1 Tat protein transactivates HIV, viral and some host cell genes. Tat can be released by infected cells and acts extracellularly in the microenvironment, regulating functions of immunocompetent and mesenchymal cells. One of the most striking effects of Tat is the induction of a functional program in vascular cells related to angiogenesis and inflammation (migration, proliferation and expression of plasminogen activator inhibitor-1 and E selectin). Tat induces growth of Kaposi's sarcoma (KS) spindle cells and is angiogenic in vivo and in transgenic mice10-12. We previously reported that Tat is a direct angiogenic factor and noted the Tat arginine- and lysine-rich sequence is similar to that of other potent angiogenic growth factors, such as vascular endothelial growth factor-A (VEGF-A). It is possible that Tat mimics one of these factors by interacting with its growth factor tyrosine kinase receptor. Here we demonstrate that Tat specifically binds and activates the Flk-1/kinase insert domain receptor (Flk-1/KDR), a VEGF-A tyrosine kinase receptor (for review see ref. 13), and that Tat-induced angiogenesis is blocked by agents blocking the Flk-1/KDR receptor. Endothelial cell stimulation by Tat occurs in the absence of activation of FLT-1, another VEGF-A tyrosine kinase receptor.
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PMID:The angiogenesis induced by HIV-1 tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. 894 38

Venous malformations (VMs), the most common errors of vascular morphogenesis in humans, are composed of dilated, serpiginous channels. The walls of the channels have a variable thickness of smooth muscle; some mural regions lack smooth muscle altogether. A missense mutation resulting in an arginine-to-tryptophan substitution at position 849 in the kinase domain of the receptor tyrosine kinase TIE2 segregates with dominantly inherited VM in two unrelated families. Using proteins expressed in insect cells, we demonstrate that the mutation results in increased activity of TIE2. We conclude that an activating mutation in TIE2 causes inherited VMs in the two families and that the TIE2 signaling pathway is critical for endothelial cell-smooth muscle cell communication in venous morphogenesis.
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PMID:Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. 898 Feb 21

Germline mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. The RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634-->Arg) and the unique MEN 2B mutation (Met918-->Thr) in two RET isoforms of 1114 and 1072 amino acids which differ in the carboxy-terminus part. Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutation was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimulated the most prominent neurite outgrowth in PC12 cells, while the short RET isoform counterpart elicited a very weak differentiation effect in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins involved the engagement of a Ras-dependent pathway. These findings provide evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activating MEN 2 mutation.
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PMID:Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations. 901 12

Germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (2A and 2B) and familial medullary thyroid carcinoma. On the other hand, somatic point mutations of RET have been described in a subset of sporadic medullary thyroid carcinomas (MTCs). We examined tumor and blood DNA of thirteen apparently sporadic MTC patients for mutations in RET exons 10, 11, 13, 15 and 16 to determine whether they had true sporadic tumors or either de novo or occult germline mutations. Three different somatic missense mutations were documented in seven patients. In five patients a mutation in exon 16, codon 918, (ATG-->ACG) causing a Met-->Thr substitution was found. In the remaining two patients the mutation affected exon 11: codon 630 in one case and codon 634 in the other. In both cases a T-->C transversion was identified causing a Cys-->Arg substitution. In conclusion, absence of a germline mutation in RET exons 10, 11, 13 or 16 is evidence against an inherited form in all cases. In seven patients, identification of a somatic mutation supported the previous clinical diagnosis of sporadic medullary thyroid carcinoma; in one of them we identified a hitherto undescribed somatic point mutation at codon 630.
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PMID:Molecular analysis of the RET proto-oncogene in patients with sporadic medullary thyroid carcinoma: a novel point mutation in the extracellular cysteine-rich domain. 915 Jul 4

Thirty percent of human breast cancers have amplification of ERBB2, often in conjunction with mutations in p53. The most common p53 mutation in human breast cancers is an Arg-to-His mutation at codon 175, an allele that functions in a dominant oncogenic manner in tumorigenesis assays and is thus distinct from loss of p53. Transgenic mice expressing mouse mammary tumor virus-driven neu transgene (MMTV-neu) develop clonal mammary tumors with a latency of 234 days, suggesting that other events are necessary for tumor development. We have examined the role of mutations in p53 in tumor development in these mice. We have found that 37% of tumors arising in these mice have a missense mutations in p53. We have directly tested for cooperativity between neu and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MMTV-neu and 172Arg-to-His p53 mutant (p53-172H). In these bitransgenic mice, tumor latency is shortened to 154 days, indicating strong cooperativity. None of the nontransgenic mice or the p53-172H transgenic mice developed tumors within this time period. Tumors arising in the p53-172H/neu bitransgenic mice were anaplastic and aneuploid and exhibited increased apoptosis, in distinction to tumors arising in p53-null mice, in which apoptosis is diminished. Further experiments address potential mechanisms of cooperativity between the two transgenes. In these bitransgenic mice, we have recapitulated two common genetic lesions that occur in human breast cancer and have shown that p53 mutation is an important cooperating event in neu-mediated oncogenesis.
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PMID:neu/ERBB2 cooperates with p53-172H during mammary tumorigenesis in transgenic mice. 915 14

Vascular endothelial growth factor (VEGF) receptor KDR (kinase-insert-domain-containing receptor) is linked to endothelial cell proliferation, and VEGF receptor Flt-1 (fms-like tyrosine kinase) is essential for the organization of embryonic vasculature. Flt-1 is also known to be expressed on adult endothelial and trophoblast cells, although its function has not yet been established. Herein we report that human trophoblast and endothelial cells contain functional Flt-1 receptors for VEGF that trigger the synthesis and release of nitric oxide (NO) by the activation of constitutive NO synthase (cNOS). In first-trimester human trophoblast cells isolated by chorionic villous sampling, VEGF165 stimulated NO release in a concentration- and time-dependent manner, with a maximal increase of 60% (in comparison to basal release levels) occurring within 30 minutes (basal: 1342 pmol/ml; VEGF (10 ng/ml): 2162 pmol/ml; p < 0.001), as measured by an NO chemiluminescence analyzer. VEGF20, a peptide fragment that is composed of the first 20 amino acids at N-terminus, displayed properties of a partial agonist. VEGF165- and VEGF20-mediated NO biosynthesis was attenuated by NG-nitro-L-arginine in a concentration-dependent fashion, indicating NOS activation. VEGF-neutralizing anti-VEGF monoclonal antibody significantly inhibited VEGF-mediated NO release (p < 0.001), and the addition of a neutralizing anti-Flt-1 antibody inhibited the response by 79.6% +/- 7.59%, an effect found to be reversible with higher concentrations of VEGF. In contrast, anti-KDR antibody had no significant inhibitory effect. RT-PCR confirmed the presence of mRNA encoding the Flt-1 and KDR receptors as well as the endothelial form of cNOS in trophoblast cells. VEGF165-stimulated NO release was inhibited by genistein (5 microM; p < 0.001) as well as by the removal of calcium from the extracellular environment (p < 0.001), which suggests the contingency of this process on tyrosine phosphorylation and extracellular calcium, respectively. Addition of sodium nitroprusside, an NO donor, inhibited trophoblast DNA synthesis in a concentration-dependent manner, as measured by [3H]thymidine incorporation, without affecting cell viability. VEGF under maximal NO production had no mitogenic activity, suggesting that trophoblast-derived NO may limit trophoblast proliferation. Endogenous trophoblast DNA synthesis increased 3-fold in the presence of anti-Flt-1 antibody but not in the presence of anti-KDR antibody, suggesting that Flt-1 functions as a growth suppressive receptor to counteract the proliferative actions of KDR. Levels of immunoreactive endothelial cNOS were markedly increased in growth-restricted placentae (n = 4) in comparison to those of normal (n = 5) placentae, which may account for the relatively small-sized placentae associated with intrauterine growth restriction. VEGF165 stimulated NO release via phosphorylation of the Flt-1 receptor, indicating that VEGF may be an autocrine regulator of NO biosynthesis by aiding trophoblast penetration into spinal arterioles during the first trimester and preventing platelet aggregation within the placenta. Finally, the activation of Flt-1 receptor suppressed trophoblast DNA synthesis within the placenta via NO.
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PMID:Role of VEGF receptor-1 (Flt-1) in mediating calcium-dependent nitric oxide release and limiting DNA synthesis in human trophoblast cells. 919 54

The abilities of isolates of saprophytes (Neurospora crassa, Aspergillus nidulans), an opportunistic human pathogen (Aspergillus fumigatus), an opportunistic insect pathogen (Aspergillus flavus), plant pathogens (Verticillium albo-atrum, Verticillium dahliae, Nectria haematococca), a mushroom pathogen (Verticillium fungicola) and entomopathogens (Verticillium lecanii, Beauveria bassiana, Metarhizium anisopliae) to utilize plant cell walls and insect cuticle components in different nutrient media were compared. The pathogens showed enzymic adaptation to the polymers present in the integuments of their particular hosts. Thus, the plant pathogens produced high levels of enzymes capable of degrading pectic polysaccharides, cellulose and xylan, as well as cutinase substrate, but secreted little or no chitinase and showed no proteolytic activity against elastin and mucin. The entomopathogens and V. fungicola degraded a broad spectrum of proteins (including elastin and mucin) but, except for chitinase, cellulase (V. lecanii and V. fungicola only) and cutinase (B. bassiana only), produced very low levels of polysaccharidases. The saprophytes (Neu. crassa and A. nidulans) and the opportunistic pathogens (A. fumigatus and A. flavus) produced the broadest spectrum of protein and polysaccharide degrading enzymes, indicative of their less specialized nutritional status. V. lecanii and V. albo-atrum were compared in more detail to identity factors that distinguish plant and insect pathogens. V. albo-atrum, but not V. lecanii, grew well on different plant cell wall components. The major class of proteases produced in different media by isolates of V. albo-atrum and V. dahliae were broad spectrum basic (pI > 10) trypsins which degrade Z-AA-AA-Arg-NA substrates (Z, benzoyl; AA, various amino acids; Na, nitroanilide), hide protein azure and insect (Manduca sexta) cuticles. Analogous peptidases were produced by isolates of V. lecanii and V. fungicola but they were specific for Z-Phe-Val-Arg-NA. V. albo-atrum and V. dahliae also produced low levels of neutral (pI ca 7) and basic (pI ca 9.5) subtilisin-like proteases active against a chymotrypsin substrate (Succinyl-Ala2-Pro-Phe-NA) and insect cuticle. In contrast, subtilisins comprised the major protease component secreted by V. lecanii and V. fungicola. Both V. lecanii and V. albo-atrum produced the highest levels of subtilisin and trypsin-like activities during growth on collagen or insect cuticle. Results are discussed in terms of the adaptation of fungi to the requirements of their ecological niches.
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PMID:Adaptation of proteases and carbohydrates of saprophytic, phytopathogenic and entomopathogenic fungi to the requirements of their ecological niches. 920 74


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