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)

First member of Ets gene family was discovered a decade ago by studying avian erythroblastosis virus, E26. This virus encodes a tripartite protein gag-myb-ets with a molecular weight of 135 kDa. Subsequently, a series of cellular Ets genes were isolated (Ets-1, Ets-2, Erg, Elk-1, Sap-1, PEA-3, PU.1, Fli-1, Pok/Yan, Etv-1 etc.). These genes share sequence homology to E26 Ets gene (v-ets or viral ets). Ets genes are highly conserved in phylogenetically divergent species from Drosophila to man. Mammalian Ets genes are located on different chromosomes. Ets gene products are transcriptionally active sequence-specific DNA binding proteins and are differentially regulated. Ets genes are involved in certain chromosomal translocations leading to the formation of chimeric fusion proteins that are associated with certain leukemias and soft tissue cancers. Ets genes also have a role in T-cell development and molecular and genetic analysis of Down Syndrome patients have implicated the human Ets-2 and Erg genes in the disease. Down Syndrome afflicted patients have immunologic and thymic disorders as well as a greater risk for leukemic disease. Thus, Ets genes having homology to viral oncogenes, may be instrumental in regulating cellular growth and differentiation, as well as organismal development. Alteration of these genes and their products may cause deregulation of normal cell growth and differentiation and result in a disease.
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PMID:Ets oncogene family. 931 29

Despite significant advances in understanding the genetic background in Hirschsprung's disease (HD), the majority of cases are believed to be multigenic and multifactorial. Conditions associated with an increased risk of HD suggest some common inherited factor and include Down's syndrome, Waardenburg syndrome (WS), dominant sensorineural deafness, neurofibromatosis, neuroblastoma, phaechromocytoma, the MEN type 2B syndrome, and other abnormalities. The reported incidence of Down's syndrome in HD is approximately 2%, but the range varies from 2% to 15%. WS, on the other hand, is one of a number of uncommon human conditions in which pigmentary disturbances are associated with sensorineural deafness. HD mutations have been mapped to a number of genes, i.e., RET proto-oncogene, at 10q11.2; the recessive EDNRB gene, located at 13q22; its ligand endothelin 3 (EDN3); and the glial cell line-derived neurotrophic factor (GDNF) in humans. Mutations of known genes appear to account for only a relatively small number of HD cases (20% in the case of RET). GDNF may modulate the disease phenotype by interacting with other susceptibility loci (e.g., RET). The genetic aspects of HD occurring in association with trisomy 21 and WS are reviewed. Clinical presentation, diagnosis, treatment and long-term outcome in this patient group are evaluated. Additional data are presented on 12 children with Down's syndrome out of 408 surgically treated HD patients. The role of associated anomalies is evaluated, and an increased susceptibility to severe enterocolitis associated with a high mortality rate is reported. Surgical correction can be achieved, but patients may require some form of ongoing help to facilitate acceptable bowel function. The decision as to the nature and timing of the surgical correction must be individualized.
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PMID:Hirschsprung's disease: genetic and functional associations of Down's and Waardenburg syndromes. 971 53

We have used FISH to determine the level of synchronisation in replication timing of four pairs of alleles, unrelated to chromosome 21 (p53, HER2, RB1, and c-myc), in foetal (amniotic fluid) cell samples of Down syndrome and in normal foetuses. All samples derived from the Down syndrome subjects showed large temporal differences in replication timing, in contrast to the high level of synchrony shown in all samples of normal individuals. Thus, as judged by four independent loci which are not associated with chromosome 21, the additional chromosome in the Down syndrome genome induces changes in the replication pattern of an allelic pair: from a synchronous pattern characteristic to concomitantly expressed alleles to an unsynchronised one shown by alleles displaying an allele-specific mode of expression.
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PMID:Asynchronous replication of allelic loci in Down syndrome. 978 Oct 44

We report on a male newborn infant, a compound carrier of heterozygous mutations in the FGFR3 gene causing achondroplasia and hypochondroplasia. The mother has achondroplasia and carries the common G1138 (G380R) mutation in the FGFR3 gene; the father has hypochondroplasia due to the C1620A (N540K) mutation in the same gene. The fetus was found to carry both mutations diagnosed prenatally by amniocentesis at 17.6 weeks of gestation, following maternal serum screening which showed an increased risk for Down syndrome (1:337). Detailed fetal ultrasound studies showed a large head, short limbs, and a small chest at 22 weeks of gestation. The changes were more severe than those of either achondroplasia or hypochondroplasia. The patient was born by cesarean section at 38 weeks of gestation and had rhizomelic shortness of the upper and lower limbs with excess skin folds, large head, enlarged fontanelles, frontal bossing, lumbar gibbus, trident position of the fingers, and a narrow chest with a horizontal line of demarcation at the narrowest area of the chest. Skeletal radiographs showed shortness of the long bones and flare of metaphyses. He had respiratory difficulties and was treated with nasal prongs. Seizures developed on day 2 of life and recurred on day 9 and responded to treatment with phenobarbital. Brain computed tomographic scan showed possible grey matter heterotopia, partial agenesis of the corpus callosum, and cortical dysplasia. To our knowledge, there are only two previously published cases of compound heterozygous achondroplasia-hypochondroplasia patients. The diagnosis was confirmed by DNA mutation analysis of the FGFR3 gene in both cases.
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PMID:Compound heterozygosity for the Achondroplasia-hypochondroplasia FGFR3 mutations: prenatal diagnosis and postnatal outcome. 1036 Mar 93

We report the case of a boy with achondroplasia and i(21q) Down syndrome. Besides craniofacial features typical in Down syndrome, the skeletal findings of achondroplasia dominate the clinical picture. The diagnosis of Down syndrome was based on clinical features and the cytogenetic finding of i(21q) trisomy 21. The diagnosis of achondroplasia was based on the presence of clinical and radiographic findings and confirmed by the presence of a common FGFR3 gene mutation (Gly380Arg) detected by restriction enzyme analysis and sequencing of the polymerase chain reaction products. This is the first report of achondroplasia associated with i(21q) Down syndrome.
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PMID:FGFR3 gene mutation (Gly380Arg) with achondroplasia and i(21q) Down syndrome: phenotype-genotype correlation. 1088 85

Hirschsprung's disease occurs rarely and sporadically in adult, involving males. In cases, which are manifested perinatally, the so called Hirschsprung-associated congenital anomalies (mainly central nervous system, urogenital and cardiovascular) may present (2-21%), which have not observed in adult. Mental retardation and Hirschsprung's disease more frequently are associated with Down syndrome (5-10%). The discoveries of molecular genetics in the last 4-5-years through the examination of transgenic ("knockout") mice, proved the basic role the mutation of 4 genes: the RET (receptor tyrosin kinase), a proto-oncogene, coding its ligand, the glial cell-line derived neutrophic factor (GDNF), the gene of the endothelin-B receptor (ENDRB) and the gene one of its ligand, the endothelin-3 (EDN3), in the pathogenesis of Hirschsprung's disease. In our case, the short segment Hirschsprung's disease caused respiratory and cardiac failure, which was recognized by autopsy. Besides, the severe mental retardation, the role of the long term use of antipsychotic medicines comes up in the prolongation and masking of the symptoms. The accompanied mental retardation and microcephalia in early childhood are known, which are associated anomalies with Hirschsprung's disease. In cases of Hirschsprung diseases at adults, no other associated congenital anomalies has been published. The mental retardation in Down-syndrome, in association with Hirschsprung's disease (and presumable in our case, too) is supposed to be the consequence of the mutation in the gene of GDNF. In this case, we observed, that the so called short segment H-d was accompanied at a 33 years old men patient with mental retardation (who was originated from a gypsy ethnic minority), because of it the connection of the nurses and the patient was disturbed and the main symptom of the H-d (chronic obstipation) remained hidden. The mechanic ileus was going on behind the scenes, and in addition to the cardiac failure caused the death of the patient. Practical conclusion of the case is that, Hirschsprung's disease should be suspected in all adult patients, who had severe obstipation persisting since childhood, especially in males.
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PMID:[Adult Hirschsprung's disease with mental retardation and microcephaly]. 1096 5

Acute leukemia is the most common form of childhood cancer and is the primary cause of cancer-related mortality in children. In the United approximately 3250 cases are diagnosed annually in children and adolescents younger than 20 years, of whom 2400 have acute lymphoblastic leukemia (ALL). Treatment results in childhood ALL continue to improve, and the expected current cure rates approach 75 to 80% of all children with ALL, including T-ALL and mature B-cell ALL, the two variants that, not too long ago, had a considerably poorer prognosis compared with the common form of BpALL. The most significant new development in the past 2 years has been the development of further evidence for fetal origin of childhood leukemias, and additional evidence to support the notion that postnatal events modulating the events of immune-mediated elimination of these leukemic clones play a major role in the eventual development of clinical disease. Other epidemiologic developments include (1) increased appreciation of the role of drug-metabolizing enzymes, both in determining the predisposition to leukemia and response to therapy; and (2) both clinical observations and gene expression studies seeming to identify a new approach to the evaluation and treatment of children with MLL (11q23) rearrangements. A most remarkable new development in the induction therapy of childhood leukemia and lymphoma in the United States is the use of urate oxidase for prevention of tumor lysis syndrome and the associated uric acid nephropathy. Drug resistance, determined either on leukemic blast cells in vitro or by studies of MRD, is being looked at critically in an effort to improve the treatment results further. Consolidation with HDMTX has gained wider popularity with the realization that effective CNS prophylaxis can be achieved with intrathecal therapy plus HDMTX for consolidation. In contrast to ALL, the progress in the therapy of acute myeloid leukemia (AML) lags behind, with cure rates of approximately 40 to 50%. There is no convincing evidence for substitution of daunorubicin with other anthracyclines, nor evidence for using high-dose cytarabine during induction in childhood AML. Rather, a 3 + 10 regimen with total daunorubicin 180 mg/m2 and cytarabine 100 to 200 mg/2 for 10 days appears to yield the best results. The most important component of the postremission chemotherapy continues to be several courses of high-dose cytarabine. The results from the MRC 10, LAME 89/91 studies and the recent BFM 93 trial with high-dose cytarabine and mitoxantrone suggest that there may be some benefit to including this combination in the postremission phase of AML. Despite these improvements in chemotherapy, allogeneic BMT from a matched family donor remains the best option for most patients (excluding Down syndrome, APL, and possibly those with inv16). Newer prognostic markers of interest include FLT3/ITD and minimal residual disease at the end of induction therapy.
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PMID:Recent advances in pediatric acute lymphoblastic and myeloid leukemia. 1249 Jul 58

Down syndrome is the most common birth defect associated with mental retardation. Identifying proteins that are aberrantly expressed therefore helps to understand how chromosomal imbalance leads to subnormal intelligence in Down syndrome. In the present study, we generated a fetal brain map with the use of an analytical method based on two-dimensional electrophoresis coupled with mass spectrometry and searched the proteome for differential protein expression. Among 49 proteins analyzed in seven control and nine Down syndrome fetuses, we found 11 proteins that have been deregulated in cerebral cortex of fetal Down syndrome. While double-strand break repair protein rad 21 homologue, eukaryotic translation initiation factor 3 subunit 5, mixed lineage leukemia septin-like fusion protein-B and heat shock protein 75 were increased; beta-amyloid precursor-like protein 1, tropomyosin 4-anaplastic lymphoma kinase fusion oncoprotein type 2, Nck adaptor protein 2, Src homology domain growth factor receptor bound 2-like endophilin B2, beta tubulin, septin 7 and hematopoietic stem/progenitor cells 140 were decreased. The current data suggest that misexpression of proteins that have functions ranging from signaling to cellular structural organization could contribute to or reflect brain dysgenesis in Down syndrome.
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PMID:Aberrant protein expression in cerebral cortex of fetus with Down syndrome. 1459 56

Dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) is the human homologue of the Drosophila mnb (minibrain) gene. In Drosophila, mnb is involved in postembryonic neurogenesis. In human, DYRK1A maps within the Down syndrome critical region of chromosome 21 and is overexpressed in Down syndrome embryonic brain. Despite its potential involvement in the neurobiological alterations observed in Down syndrome patients, the biological functions of the serine/threonine kinase DYRK1A have not been identified yet. Here, we report that DYRK1A overexpression potentiates nerve growth factor (NGF)-mediated PC12 neuronal differentiation by up-regulating the Ras/MAP kinase signaling pathway independently of its kinase activity. Furthermore, we show that DYRK1A prolongs the kinetics of ERK activation by interacting with Ras, B-Raf, and MEK1 to facilitate the formation of a Ras/B-Raf/MEK1 multiprotein complex. These data indicate that DYRK1A may play a critical role in Ras-dependent transducing signals that are required for promoting or maintaining neuronal differentiation and suggest that overexpression of DYRK1A may contribute to the neurological abnormalities observed in Down syndrome patients.
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PMID:DYRK1A enhances the mitogen-activated protein kinase cascade in PC12 cells by forming a complex with Ras, B-Raf, and MEK1. 1591 94

Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL), characterized by expression of truncated GATA1 transcription factor protein (GATA1s) due to somatic mutation. The treatment outcome for DS-AMKL is more favorable than for AMKL in non-DS patients. To gain insight into gene expression differences in AMKL, we compared 24 DS and 39 non-DS AMKL samples. We found that non-DS-AMKL samples cluster in two groups, characterized by differences in expression of HOX/TALE family members. Both of these groups are distinct from DS-AMKL, independent of chromosome 21 gene expression. To explore alterations of the GATA1 transcriptome, we used cross-species comparison with genes regulated by GATA1 expression in murine erythroid precursors. Genes repressed after GATA1 induction in the murine system, most notably GATA-2, MYC, and KIT, show increased expression in DS-AMKL, suggesting that GATA1s fail to repress this class of genes. Only a subset of genes that are up-regulated upon GATA1 induction in the murine system show increased expression in DS-AMKL, including GATA1 and BACH1, a probable negative regulator of megakaryocytic differentiation located on chromosome 21. Surprisingly, expression of the chromosome 21 gene RUNX1, a known regulator of megakaryopoiesis, was not elevated in DS-AMKL. Our results identify relevant signatures for distinct AMKL entities and provide insight into gene expression changes associated with these related leukemias.
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PMID:Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. 1649 68


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