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)

To facilitate the positional cloning of the breast-ovarian cancer gene BRCA1, we constructed a high-density genetic map of the 8.3-cM interval between D17S250 and GIP on chromosome 17q12-q21. Markers were mapped by linkage in the CEPH and in extended kindreds in our breast cancer series. The map comprises 33 ordered polymorphisms, including 12 genes and 21 anonymous markers, yielding an average of one polymorphism every 250 kb. Twenty-five of the markers are PCR-based systems. The order of polymorphic genes and markers is cen-D17S250-D17S518-HER2-THRA1-RARA-D17S80 -KRT10-[D17S800-D17S857]-GAS- D17S856-EDH17B-D17S855-D17S859-D17S858-[++ +PPY-D17S78]-D17S183-EPB3-D17S579- D17S509-[D17S508-D17S190 = D17S810]-D17S791-[D17S181 = D17S806]-D17S797- HOX2B-GP3A-[D17S507 = GIP]-qter. BRCA1 lies in the middle of the interval, between THRA1 and D17S183. Markers from this map can be used to determine whether cancer is linked to BRCA1 in families, to evaluate whether tumors have lost heterozygosity at loci in the region, and to identify probes for characterizing chromosomal rearrangements from patients and from tumors.
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PMID:High-density genetic map of the BRCA1 region of chromosome 17q12-q21. 824 78

In order to pinpoint the locale of the gene for early-onset familial breast and ovarian cancer (BRCA1), polymorphisms were developed within the locus for thyroid hormone receptor alpha (THRA1) and for several anonymous sequences at chromosome 17q12-q21. The THRA1 polymorphism is a dinucleotide repeat with 10 alleles and heterozygosity.79. Gene mapping in extended families with inherited, early-onset breast and ovarian cancer indicates that BRCA1 is distal to THRA1 and proximal to D17S183 (SCG43), an interval of < 4 cM. This locale excludes HER2, THRA1, WNT3, HOX2, NGFR, PHB, COLIA1, NME1, and NME2 as candidates for BRCA1 but does not exclude RARA or EDH17B. Resolving the remaining recombination events in these families by new polymorphisms in the THRA1-D17S183 interval will facilitate positional cloning of the breast-ovarian cancer gene on chromosome 17q12-q21.
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PMID:THRA1 and D17S183 flank an interval of < 4 cM for the breast-ovarian cancer gene (BRCA1) on chromosome 17q21. 846 Jun 37

Canids are unusual among mammals in the large degree to which their karyotypes have diverged during speciation. In many instances, chromosome segments from different species share cytogenetic homology, and a presumed phylogenetic tree of Canid evolution can be constructed based on the relative shuffling of chromosomal elements. In this study, four gene probes (myeloperoxidase [MPO], Miller-Dieker [MDCR], ERBB2, and retinoic acid receptor alpha [RARA]) from human chromosome 17 were used in fluorescence in situ hybridizations with chromosomes of three different Canids: two subspecies of the Asiatic raccoon dog (Nyctereutes) and the domestic dog (Canis familiaris). The Nyctereutes subspecies have widely diverged karyotypes (2n = 38 versus 2n = 54) and Canis familiaris has a large number (2n = 78) of chromosomes. This study confirms the identity of two shared chromosomes of Nyctereutes. The Japanese raccoon dog chromosome 13 shares linkage with the Chinese raccoon dog chromosome 5. Both of these Nyctereutes chromosomes share synteny with human chromosome 17. Human chromosome 17 shares linkage with Canis familiaris chromosome 23. The relative order and spacing of the genes mapped in these species suggests the occurrence of chromosome rearrangements, most notably inversions, during the evolution of these animals.
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PMID:Shared synteny of human chromosome 17 loci in Canids. 889 20

We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith-Magenis syndrome (SMS). This 11-year-old boy had short stature, midfacial hypoplasia, and behavioral problems characteristic of this syndrome. Cytogenetic analysis showed that the proximal long arm of a chromosome 17 (q11.2-q21.3) was inserted into its short arm at p11.2, resulting in an apparent deletion of the SMS critical region [ins(17)(p11.2q11.2q21.3)]. Fluorescence in situ hybridization studies (FISH) demonstrated that the inserted segment included both the ERBB2 and RARA loci, and dual color hybridizations defined the insertion as direct, with ERBB2 located more proximally on the short arm of the der(17). The resulting deletion of the short arm included loci c130G3, D17S258, FLI, and D17S29, while the more proximal loci, D17S446 and D17S58, remained apparently unaffected and in their native locations. The CMT1A locus also remained in its native location on the short arm of the metacentric der(17) chromosome. A de novo intrachromosomal insertional rearrangement of chromosome 17 in a case of SMS has not been reported previously and further illustrates the instability of this chromosomal region.
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PMID:Smith-Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11.2. 955 89

Using the hybrid cell lines pig-American mink, cow-American mink, and sheep-American mink, the localization of some genes included in a large conservative block localized on human chromosome (chr) 17 was performed by means of electrophoresis of proteins and Southern blot hybridization. Genes NF1, RARA, PRKCA, and ERBB2 were assigned to chr 12 in swine; TK1 and UMPH2, to chr 19 in cattle; and TK1, UMPH2, and PEPA, to chr 11 in sheep. The conserved synteny of these genes in three representatives of the order Artiodactyla was shown.
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PMID:[Chromosome localization and analysis of synteny analysis of some genes in swine, cattle, and sheep (Artiodactyla)]. 987 8

A patient is described with myelodysplastic syndrome (MDS) progressing to acute myeloid leukemia (AML) FAB M4. Cytogenetic analysis revealed an unusual rearrangement between chromosomes 9 and 17, leading to a dicentric chromosome with an insertion of material of unknown origin between both chromosomes. By fluorescence in situ hybridization (FISH), the insertion was shown to be an amplification of part of 17q, involving ERBB2, RARA, and TOP2A genes. The median copy number of ERBB2, RARA, and TOP2A genes in the tumor cells was six (range: 4--10). Only one copy of the MPO gene at 17q21.3 was detected, suggesting a deletion of the telomeric part of 17q. To our knowledge, this is the first report of a 17q amplification in AML.
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PMID:Amplification of ERBB2, RARA, and TOP2A genes in a myelodysplastic syndrome transforming to acute myeloid leukemia. 1142 59

Because a previous study by conventional cytogenetics had revealed a nullisomy 17 in the breast cancer cell line EFM-19, we analysed that cell line by SKY-FISH and by FISH using different probes derived from chromosome 17. A bicolor FISH using a HER2-specific probe and a chromosome 17 centromeric probe showed five HER2 and six centromeric signals all appearing on different chromosomes A further bicolor FISH using a chromosome 17-specific painting probe and a HER2-specific probe revealed that the HER2 signals were always localized within chromosome 17 segments constituting part of structurally altered chromosomes as deduced from their G-banding. Further FISH analyses using single-locus probes of chromosome 17, i.e., for MDS, p53, SMS and RARA, showed that all five chromosome 17 painting segments contained material from the long arm but only two painting segments had additional material from the short arm. A SKY-FISH confirmed the results of the chromosome 17 painting by FISH, except for one structurally altered chromosome showing additional chromosome 17 material detected by the SKY experiment. These results allow us to conclude that, in this cell line, polysomy 17 has preceeded the fragmentation of chromosome 17 leading to amplification of small parts of that chromosome as well as to extended losses. As to a general mechanism, polysomy 17 and a fragility of this, chromosome in breast cancer cells may not only account for part of the cases with HER2 amplification but, at the same time, may further support malignant progression due to the loss of tumor suppressor genes as e.g. p53.
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PMID:Molecular-cytogenetic analysis of fragmentation of chromosome 17 in the breast cancer cell line EFM-19. 1217 75

The PML-RAR alpha fusion protein is central to the pathogenesis of acute promyelocytic leukemia (APL). Expression of this protein in transgenic mice initiates myeloid leukemias with features of human APL, but only after a long latency (8.5 months in MRP8 PML-RARA mice). Thus, additional changes contribute to leukemic transformation. Activating mutations of the FLT3 receptor tyrosine kinase are common in human acute myeloid leukemias and are frequent in human APL. To assess how activating mutations of FLT3 contribute to APL pathogenesis and impact therapy, we used retroviral transduction to introduce an activated allele of FLT3 into control and MRP8 PML-RARA transgenic bone marrow. Activated FLT3 cooperated with PML-RAR alpha to induce leukemias in 62 to 299 days (median latency, 105 days). In contrast to the leukemias that arose spontaneously in MRP8 PML-RARA mice, the activated FLT3/PML-RAR alpha leukemias were characterized by leukocytosis, similar to human APL with FLT3 mutations. Cytogenetic analysis revealed clonal karyotypic abnormalities, which may contribute to pathogenesis or progression. SU11657, a selective, oral, multitargeted tyrosine kinase inhibitor that targets FLT3, cooperated with all-trans retinoic acid to rapidly cause regression of leukemia. Our results suggest that the acquisition of FLT3 mutations by cells with a pre-existing t(15;17) is a frequent pathway to the development of APL. Our findings also indicate that APL patients with FLT3 mutations may benefit from combination therapy with all-trans retinoic acid plus an FLT3 inhibitor.
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PMID:A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. 1251 27

Acute promyelocytic leukemia (APL) is characterized by the PML-RARA fusion gene. To identify genetic changes that cooperate with PML-RARA, we performed spectral karyotyping analysis of myeloid leukemias from transgenic PML-RARA mice and from mice coexpressing PML-RARA and BCL2, IL3, activated IL3R, or activated FLT3. A cooperating mutation that enhanced survival (BCL2) was not sufficient to complete transformation and was associated with multiple numeric abnormalities, whereas cooperating mutations that deregulated growth and enhanced survival were associated with normal karyotypes (IL3) or simple karyotypic changes (IL3R, FLT3). Recurring abnormalities included trisomy 15 (49%), trisomy 8 (46%), and -X/-Y (54%). The most common secondary abnormality in human APL is +8 or partial trisomy of 8q24, syntenic to mouse 15. These murine leukemias have a defined spectrum of changes that recapitulates, in part, the cytogenetic abnormalities found in human APL. Our results demonstrate that different cooperating events may generate leukemia via different pathways.
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PMID:Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice identify cooperating events and genetic pathways to acute promyelocytic leukemia. 1268 27

MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as internal duplication and breakage induced by topoisomerase II inhibitors. In adult AML, FLT3 internal tandem duplications (ITDs) are more common in cases with MLL intragenic abnormalities (33%) than those with MLL translocation (8%). Mutation/deletion involving FLT3 D835 are found in more than 20% of cases with MLL intragenic abnormalities compared with 10% of AML with MLL translocation and 5% of adult AML with normal MLL status. Real-time quantification of FLT3 in 141 cases of AML showed that all cases with FLT3 D835 express high level transcripts, whereas FLT3-ITD AML can be divided into cases with high-level FLT3 expression, which belong essentially to the monocytic lineage, and those with relatively low-level expression, which predominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leukemias with AML1-ETO or CBFbeta-MYH11 were virtually restricted to cases with variant CBFbeta-MYH11 fusion transcripts and/or atypical morphology. These data suggest that the FLT3 and MLL loci demonstrate similar susceptibility to agents that modify chromatin configuration, including topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Variant CBFbeta-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
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PMID:FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. 1279 58


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