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)

By somatic cell fusion studies between noninvasive mouse T-lymphoma cells and invasive human activated normal T-cells we have previously shown that the genetic information responsible for the induction of invasive and metastatic potential in interspecies T-cell hybrids is located on human chromosome 7. Apparently, genes derived from normal activated T-cells are dominantly expressed in the hybrids and control the invasive and, as a consequence, metastatic potential of these T-lymphoma cells. To sublocalize the invasion-inducing locus on chromosome 7 we have generated hybrids that harbor only specific regions of human chromosome 7 with or without a small fragment of human chromosome 21. Analysis of these hybrids revealed that the invasion-inducing locus maps to 7p12----cen. The human DNA complement of the hybrids was confirmed by Southern blot analysis using a large panel of chromosome 7-specific DNA probes. Several of these genes could be further sublocalized. These included: ARAF2 to 7p12----cen, D7S21 to 7pter----p12, ACTB to 7p15----p12, EGFR to 7p12, MDH2 to 7cen----q22, and PDGFA to 7pter----p15.
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PMID:Sublocalization of an invasion-inducing locus and other genes on human chromosome 7. 150 15

Transforming growth factor-beta (TGF-beta)can induce the cyclin-dependent kinase inhibitors p21 and p15 in a variety of cell types. We have shown previously that Smad3 is required for the growth inhibitory activity of TGF-beta, whereas overexpression of Smads is not sufficient to activate the expression of p21 in HaCaT cells. These data suggest that an additional signaling pathway may be involved in stimulating p21 in HaCaT cells. Given the recent finding that the mitogen-activated protein kinase (MAPK) pathway can cause p21 induction and arrest cells, we examined the involvement of this pathway for p21 and p15 induction by TGF-beta. We found that TGF-beta can regulate the MAPK pathway, leading to the increased transactivation ability of transcription factor Elk. Constitutively active components in the MAPK pathway activate p21 expression, and inhibitors or dominant negative constructs for the MAPK pathway significantly decrease p21 induction by TGF-beta. Both constitutively active MEK and inhibitors for MEK have no effect on Smad activity, including DNA binding, localization, and interaction with coactivator p300/CBP. These findings suggest that the MAPK pathway may be an independent pathway that is involved in p21 and p15 induction by TGF-beta.
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PMID:The MEK pathway is required for stimulation of p21(WAF1/CIP1) by transforming growth factor-beta. 1058 6

Epidemiological studies have shown that inhalation of radon, a radioactive gas, is associated with an increased risk for lung cancer. We have developed a model of radon-induced rat lung tumors to characterize cytogenetic and molecular events involved in radon-induced lung tumorigenesis. Using comparative genomic hybridization (CGH), gains and losses of genetic material were investigated in a series of 13 carcinomas and four adenomas of the lung. Frequent losses occurred at 4q12-21, 5q11-33, and 15q, which are homologous to human chromosome (HSA) bands 7q21-36, 1p31-36/9p21-31, and 13q14.1-14.3/3p14.2, respectively. These regions are frequently (30-80%) deleted in human lung cancer and contain tumor suppressor genes or proto-oncogenes such as MET, CDKN2A/p16/MTS1, CDKN2B/p15/MTS2, FHIT, and RB1 or yet to be identified genes. Frequent gains involved 6, 7q34-qter, and 19q; chromosomes 6 and 7 being homologous to human 2p21-25 and 8q21-24 where the MYCN and MYC oncogenes are located. The genetic similarities between rat and human lung cancer suggest common underlying mechanisms for tumor evolution in both species. Moreover, cytogenetic and molecular genetic analyses of radon-induced rat lung tumors could help to better understand the development and progression of radon-induced lung cancer in man.
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PMID:CGH analysis of radon-induced rat lung tumors indicates similarities with human lung cancers. 1091 87

Multiple myeloma (MM) is a B-cell neoplasm characterized by bone marrow infiltration with malignant plasma cells, which synthesize and secrete monoclonal immunoglobulin (Ig) fragments. Despite the considerable progress in the understanding of MM biology, the molecular basis of the disease remains elusive. The initial transformation is thought to occur in a postgerminal center B-lineage cell, carrying a somatically hypermutated Ig heavy chain (IGH) gene. This plasmablastic precursor cell colonizes the bone marrow, propagates clonally and differentiates into a slowly proliferating myeloma cell population, all under the influence of specific cell adhesion molecules and cytokines. Production of interleukin-6 by stromal cells, osteoblasts and, in some cases, neoplastic cells is an essential element of myeloma cell growth, with the cytokine stimulus being delivered intracellularly via the Jack-STAT and ras signaling pathways. While karyotypic changes have been identified in up to 50% of MM patients, recent molecular cytogenetic techniques have revealed chromosomal abnormalities in the vast majority of examined cases. Translocations mostly involve illegal switch rearrangements of the IGH locus with various partner genes (CCND1, FGFR3, c-maf). Such events have been assigned a critical role in MM development. Mutations in coding and regulatory regions, as well as aberrant expression patterns of several oncogenes (c-myc, ras) and tumor suppressor genes (p16, p15) have been reported. Key regulators of programmed cell death (BCL-2, Fas), tumor expansion (metalloproteinases) and drug responsiveness (topoisomerase II alpha) have also been implicated in the pathogenesis of this hematologic malignancy. A tumorigenic role for human herpesvirus 8 (HHV8) was postulated recently, following the detection of viral sequences in bone marrow dendritic cells of MM patients. However, since several research groups were unable to confirm this observation, the role of HHV8 remains unclear. Translation of the advances in MM molecular biology into novel therapeutic strategies is essential in order to improve disease prognosis.
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PMID:Molecular aspects of multiple myeloma. 1110 9

A prenatal tumor located in the lumbar paravertebral area was discovered during a routine ultrasound examination at 32 weeks of pregnancy and surgically removed at 4 months of life. The histopathological diagnosis was first suggested to be an infantile desmoid fibromatosis. The tumor karyotype showed a three-way translocation involving both chromosomes 2 and a chromosome 11, t(2;11;2)(p23;p15;q31). Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 demonstrated a rearrangement, as previously described in inflammatory myofibroblastic tumors (IMTs). In light of the genetic analysis, the histopathological diagnosis was revised to IMT, although inflammatory cells were scarce. IMTs are pseudosarcomatous inflammatory lesions that primarily occur in the soft tissue and viscera of children and young adults. Our report describes for the first time the occurrence of IMT during prenatal life. The ALK rearrangement may represent the molecular definition of a subgroup of mesenchymal tumors, not always with complete morphological features of IMT, similar to the model of EWS rearrangement in the Ewing sarcoma family of tumors.
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PMID:ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation found in a prenatal myofibroblastic fibrous lesion: toward a molecular definition of an inflammatory myofibroblastic tumor family? 1128 39

A newborn baby boy was diagnosed with the mixed form of congenital mesoblastic nephroma (CMN) representing both classic and cellular histology features in the renal tumor. Additionally, the patient had skin and bone lesions consistent with multifocal involvement of a generalized infantile fibromatosis (IFS). Both skin and bone lesions were distinctly different from CMN and did not represent metastasis. The primary tumor cell line (MCH-MN-1), established from the resected right kidney tumor, had a diploid DNA content. Cytogenetic studies revealed deletion on the long arm of chromosome 3 (q21q24) and duplication on the short arm of chromosome 11 (p15). MCH-MN-1 cells expressed ETV6-NTRK3 gene fusion transcripts, characteristic of cellular and mixed forms of CMNs. The cells had high p21 and low Bax mRNA expression in the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. The high level of proliferative marker (Ki67) mRNA expression correlated well with the pluripotent nature of MCH-MN-1 in tissue culture (cell doubling time = 12.4 h). Our results showed that MCH-MN-1 might be a good model cell line for investigations on mesoblastic nephroma.
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PMID:Cytogenetic and molecular characterization of a congenital mesoblastic nephroma. 1144 43

Cytogenetic abnormalities are seen in approximately 50% of cases of myelodysplastic syndrome (MDS) and 80% of cases of secondary MDS (following chemotherapy or radiotherapy). These abnormalities generally consist of partial or complete chromosome deletion or addition (del5q, -7, +8, -Y, del20q), whereas balanced or unbalanced translocations are rarely found in MDS. Fluorescence hybridization techniques (fluorescence in situ hybridization [FISH], multiplex FISH, and spectral karyotyping) are useful in detecting chromosomal anomalies in cases in which few mitoses are obtained or rearrangements are complex. Ras mutations are the molecular abnormalities most frequently found in MDS, followed by p15 gene hypermethylation, FLT3 duplications, and p53 mutations, but none of these abnormalities are specific for MDS. The rare cases of balanced translocations in MDS have allowed the identification of genes whose rearrangements appear to play a role in the pathogenesis of some cases of MDS. These genes include MDS1-EVI1 in t(3;3) or t(3;21) translocations, TEL in t(5;12), HIP1 in t(5;7), MLF1 in t(3;5), and MEL1 in t(1;3). Genes more frequently implicated in the pathogenesis of MDS cases, such as those involving del5q, remain unknown, although some candidate genes are currently being studied. Cytogenetic and known molecular abnormalities generally carry a poor prognosis in MDS and can be incorporated into prognostic scoring systems such as the International Prognostic Scoring System.
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PMID:Chromosome and molecular abnormalities in myelodysplastic syndromes. 1150 56

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.
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PMID:Identification of four new translocations involving FGFR1 in myeloid disorders. 1155 Feb 83

Classic genetic rearrangements in papillary carcinoma of the thyroid involve the RET- or TRK proto-oncogenes. We report a novel chromosomal translocation t(3;5)(q12;p15.3), confirmed by fluorescence in situ hybridization, in a multifocal follicular variant of a papillary carcinoma of the thyroid in a 79-year-old woman, with skin metastases as a presenting symptom. Three years earlier, another cutaneous metastasis on her scalp was misdiagnosed as hidradenoma. Four tumour foci were recognized in the thyroid, two with a follicular variant of papillary carcinoma. To detect loss of heterozygosity, 14 chromosomes were investigated with 59 microsatellite markers. A clonal relationship was detected between the two foci of tumour in the thyroid gland containing follicular variant of papillary carcinoma and one of the skin lesions tested, all demonstrating loss of heterozygosity (LOH) in the same region of chromosome 22. Based on earlier reports, the low rate of LOH detected is in agreement with the diagnosis papillary carcinoma of the thyroid. Whole body scintigraphy performed after ablative therapy with radioiodine revealed multiple metastases in the lungs and skeleton. After repeated radioiodine therapy, thyroglobulin under thyroxine suppression became undetectable and post-therapeutic scintigraphy revealed important regression of metastases.
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PMID:A novel chromosomal translocation t(3;5)(q12;p15.3) and loss of heterozygosity on chromosome 22 in a multifocal follicular variant of papillary thyroid carcinoma presenting with skin metastases. 1167 39

The t(11;20)(p15;q11) is a rare but recurrent translocation that so far has been described in only four acute myeloid leukemias (AMLs), two treatment-related myelodysplastic syndromes (t-MDSs), and one case of polycythemia vera. Recently, the t(11;20) was shown to result in a fusion of the NUP98 and TOP1 genes, with expression of the NUP98/TOP1 chimera encoded by the der(11)t(11;20), but not of the reciprocal TOP1/NUP98 on the der(20)t(11;20). The genomic breakpoints were subsequently mapped to introns 13 and 7 of NUP98 and TOP1, respectively. We present here a t-MDS with a three-way variant translocation, t(10;20;11)(q24;q11;p15), that generates a der(11)t(11;20) but not a der(20)t(11;20), strongly suggesting that the der(11) harbors the critical genetic rearrangement. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a NUP98/TOP1 fusion in which exon 13 of NUP98 was fused in-frame with exon 8 of TOP1. Extra long (XL) genomic PCR and subsequent sequence analyses showed that the breakpoint in NUP98 occurred at nucleotide (nt) 3461 of intron 13, close to a MER (medium reiteration frequency interspersed repetitive element) repeat, and that the breakpoint in TOP1 was at nt 1436 of intron 7, downstream of a MIR (mammalian-wide interspersed repeats) repetitive element. Genomic XL PCR did not amplify the reciprocal TOP1/NUP98, nor was this chimera expressed, as expected from the cytogenetic finding. The present results provide further support for the involvement of the NUP98/TOP1 transcript, but not of the reciprocal one, in the development of MDS/AML. Furthermore, the three cases genomically characterized to date have all been treatment-related and have all harbored breakpoints in intron 13 of NUP98 and intron 7 of TOP1, suggesting that these introns are susceptible to chemotherapy-induced breakage.
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PMID:Expression of NUP98/TOP1, but not of TOP1/NUP98, in a treatment-related myelodysplastic syndrome with t(10;20;11)(q24;q11;p15). 1197 59


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