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)

MYC, ERBB2, MET, FGFR2, CCNE1, MYCN, WNT2, CD44, MDM2, NCOA3, IQGAP1 and STK6 loci are amplified in human gastric cancer. It has been reported that the gene corresponding to EST H16094 is co-amplified with ERBB2 gene in human gastric cancer. Here, we identified and characterized the gene corresponding to EST H16094 by using bioinformatics. BLAST programs revealed that EST H16094 was derived from the uncharacterized MGC9753 gene. Two ORFs were predicted within human MGC9753 mRNA, and ORF1 (nucleotide position 18-980 of NM_033419.1) was predicted as the coding region of human MGC9753 mRNA based on comparative genomics. Nucleotide sequence of mouse Mgc9753 mRNA was next determined in silico by modification of AK052486 cDNA (deleting C at the nucleotide position 37). Human MGC9753 and mouse Mgc9753 proteins were 320-amino-acid seven-transmembrane receptors with the N-terminal six-cysteine domain and an N-glycosylation site (85.0% total-amino-acid identity). Human MGC9753 protein showed 90.6% total-amino-acid identity with human CAB2 aberrant protein, which lacked the third-transmembrane domain of MGC9753 due to frame shifts within ORF. Human MGC9753 gene, consisting of eight exons, were clustered with PPP1R1B, STARD3, TCAP, PNMT, ERBB2, MGC14832 and GRB7 genes within the 120-kb region. PPP1R1B, STARD3, MGC9753, ERBB2 and GRB7 genes are co-amplified in several cases of gastric cancer. This is the first report on comprehensive characterization of the amplicon around the PPP1R1B-STARD3-TCAP-PNMT-MGC9753-ERBB2-MGC14832-GRB7 locus on human chromosome 17q12.
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PMID:MGC9753 gene, located within PPP1R1B-STARD3-ERBB2-GRB7 amplicon on human chromosome 17q12, encodes the seven-transmembrane receptor with extracellular six-cystein domain. 1273 7

LASP1 (also known as MLN50) gene, located centromeric to the PPP1R1B-ERBB2-GRB7 locus on human chromosome 17q12, is amplified and over-expressed in breast cancer. Here, we identified and characterized a novel LASP1-related gene, LASP2, by using bioinformatics. Nucleotide sequence of human LASP2 cDNA was determined in silico by assembling EST BF699808 and 5'-truncated FLJ39221 cDNA. Nucleotide sequence of mouse Lasp2 cDNA was derived from 1200007O21Rik cDNA. Human LASP2 (270 aa) showed 97.4% and 63.7% total-amino-acid identity with mouse Lasp2 and human LASP1, respectively. LASP2 and LASP1 were the LASP family proteins consisting of LIM domain, Nebulin repeat, and SH3 domain. LASP2 and NEBL mRNAs were transcribed from the LASP2/NEBL gene on human chromosome 10p12 due to alternative splicing. LASP2 mRNA consists of exons 1a-4a, 24, 27, and 28 of the LASP2/NEBL gene, while NEBL mRNA consists of exons 1-28. Exon 1a-4a of the LASP2/NEBL gene were more homologous to exon 1-4 of the LASP1 gene on human chromosome 17q12, while exon 1-28 of the LASP2/NEBL gene were more homologous to exons of NEB gene on human chromosome 2q23. Some part of the LASP2/ NEBL-TEM7L-ARL8-CACNB2 locus on 10p12 was paralogous to the LASP1-TEM7-CACNB1 locus on 17q12, while the other part of the LASP2/NEBL-TEM7L-ARL8-CACNB2 locus was paralogous to the NEB-ARL5-CACNB4 locus on 2q23. These facts indicate that the LASP2/NEBL-TEM7L-ARL8-CACNB2 is a chimeric locus, which might be generated through the homologous recombination between the ancestral lasp2-tem7l-cacnb2 locus and the ancestral nebl-arl8 locus. Therefore, gene fusion during evolution is one of the mechanisms to generate alternative splicing.
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PMID:Identification and characterization of LASP2 gene in silico. 1288 59

The PPP1R1B-STARD3-TCAP-PNMT-MGC9753-ERBB2-MGC14832-GRB7 locus on human chromosome 17q12 is frequently amplified in human gastric and breast cancer. We have recently identified and characterized human MGC9753 (also known as wild-type CAB2) and mouse Mgc9753. Here, we identified and characterized mouse Erbb2 gene by using bioinformatics. BLAST programs revealed that mouse AK031099 cDNA was derived from mouse Erbb2 gene. Because AK031099 cDNA showed 806 C-->A nucleotide substitution compared with mouse genome draft sequences and mouse Erbb2 ESTs, the nucleotide sequence of mouse Erbb2 cDNA was determined in silico by correcting 806 A of AK031099 cDNA to C. Nucleotide position 48-3818 of mouse Erbb2 cDNA was the coding region. Mouse Erbb2 gene, consisting of 27 exons, was located within the Ppp1r1b-Grb7 locus on the mouse chromosome 11. Mouse Erbb2 protein (1256 aa) showed 87.5% total-amino-acid identity with human ERBB2 protein, and 95.2% total-amino-acid identity with rat Erbb2 protein. Mouse Ppp1r1b-Grb7 locus and human Ppp1r1b-Grb7 locus were evolutionarily conserved in the order and the orientation of genes therein. Nucleotide and amino-acid substitution rates of Neurod2 located centromeric to the Ppp1r1b-Grb7 locus were significantly lower than others within the Ppp1r1b-Grb7 locus. This is the first report on the complete coding sequence of mouse Erbb2 gene as well as on the comprehensive comparison of Ppp1r1b-Grb7 locus within the human and mouse genomes.
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PMID:Identification and characterization of mouse Erbb2 gene in silico. 1288 24

PPP1R1B-STARD3-TCAP-PNMT-PERLD1-ERBB2-MGC14832-GRB7 locus at human chromosome 17q12 is frequently amplified in human gastric cancer and breast cancer. Here, we compared human GSDML-GSDM locus with rodent genomes by using bioinformatics. Rodent ortholog of human GSDML was not identified. Rat Gsdm gene was identified within rat genome clone CH230-28N16 (AC119462.4), and was mapped to rat chromosome 10q31. Rat Gsdm gene, consisting of 12 exons, encoded a 446-amino-acid protein, which showed 86.3% and 32.3% total-amino-acid identities with human GSDM and GSDML, respectively. Mouse Gsdm-like 1 (Gsdml1) and Gsdml2 genes were identified within mouse genome clone RP23-438D7 (AL591125.20). Gsdml1 and Gsdml2 genes were found to encode 456- and 443-amino-acid proteins, respectively. Mouse 2200001G21Rik cDNA (AK008613.1) was a partial cDNA derived from mouse Gsdml2 gene. Mouse Gsdml1 and Gsdml2 were also more homologous to human GSDM than to human GSDML. Mouse Gsdml1, Gsdml2 and Gsdm genes, existing in the tandem homologous gene cluster, was mapped to mouse chromosome 11D. Mouse Gsdml1-Gsdml2-Gsdm gene cluster was predicted to be generated due to triplication of mouse Gsdm gene, while GSDML gene was predicted to be generated due to duplication of GSDM gene. Evolutionary recombination hotspot around the GSDML-GSDM locus was closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon. The evolutionary recombination hotspot and oncogenomic recombination hotspot might be clustered around the fragile sites within the human genome.
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PMID:Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon. 1501 Aug 12

An evolutionary recombination hotspot around the GSDML-GSDM locus at human chromosome 17q21 is closely linked to an oncogenomic recombination hotspot around the PPP1R1B-STARD3-TCAP-PNMT-PERLD1 (MGC9753)-ERBB2-C17orf37 (MGC14832)-GRB7 locus at human chromosome 17q12. Here, we identified DFNA5L (GSDMDC1) gene related to GSDM and GSDML genes by using bioinformatics. Human DFNA5L gene at chromosome 8q24.3 was linked to ZC3HDC3, PP3856, EEF1D, and TIGD5 genes. NM_024736.4 (AK127941.1), AK022212.1, BC008904.2, and BC069000.1 cDNAs were derived from human DFNA5L gene. BC008904.2 was the representative human DFNA5L cDNA, while NM_024736.4 was an aberrant human DFNA5L cDNA with frame shifts due to the retention of introns 1, 3, 4, 5 and 8. Human DFNA5L mRNA was expressed in placenta, pancreatic cancer, prostate cancer, melanoma, salivary gland tumor, Jarkat T cells, and Ramos B cells. Complete coding sequence of rat Dfna5l cDNA was determined by assembling 11 exons of rat Dfna5l gene within AC120830.4 genome sequence, and that of mouse Dfna5l cDNA was derived from 1810036L03 (NM_026960.1). Exon-intron boundaries were conserved among human DFNA5L and rodent Dfna5l genes. Human DFNA5L (484 aa) showed 59.5% total-amino-acid identity with rat Dfna5l (488 aa), and 58.7% total-amino-acid identity with mouse Dfna5l (487 aa). DFNA5L orthologs were DNFA5 (GSDM) domain containing DFNA5 DC or GSDMDC proteins with Coiled-coil and Leucine zipper domains. Human DFNA5L, GSDM, GSDML, MLZE, DFNA5 and their mammalian orthologs were found to constitute the DFNA5 DC (GSDMDC) family. Because DFNA5 and MLZE are cancer-associated genes, DFNA5L, GSDM, and GSDML are predicted cancer associated genes.
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PMID:Identification and characterization of human DFNA5L, mouse Dfna5l, and rat Dfna5l genes in silico. 1528 81

DNA amplification at 17q is frequently detected in upper gastrointestinal adenocarcinomas (UGC; stomach and esophagus). In this study, we did fluorescence in situ hybridization on a tissue microarray that contained 304 UGCs and 89 normal stomach samples using a approximately 168-kb BAC clone (CTD-2019C10) that maps to 17q12-q21.1. This 168-kb region contains the following genes: PPP1R1B/DARPP-32, STARD3, TCAP, PNMT, PERLD1, ERBB2, C17orf37, and GRB7 as well as the first two exons of ZNFN1A3. DNA amplification (> or =5 signals) was detected in 85 of 282 (30%) of UGCs, and high-level amplification (> or =10 signals) was seen in 28 of 282 (10%) of all tumors. Adenocarcinomas of gastroesophageal junction and lower esophagus had the highest frequency of amplification (45%) compared with stomach tumors (27%; P = 0.04). On the other hand, 38% of tumors with intestinal-type morphology had amplification compared with 26% of diffuse-type tumors (P = 0.02). We further did quantitative real-time reverse transcription-PCR on 74 frozen tissue samples from UGCs for 11 genes located within or adjacent to the boundaries of this approximately 168-kb genomic region. These genes include all 9 genes that are fully or partially located inside the CTD-2019C10 clone as well as 2 additional adjacent genes (NEUROD and TOP2A). Overexpression of PPP1R1B/DARPP-32, TCAP, and TOP2A was seen in approximately half of the tumors, whereas STARD3 and ZNFN1A3 were rarely overexpressed (12%). Interestingly, there was a statistical correlation between expression of all 8 genes that map between PPP1R1B/DARPP-32 and GRB7, whereas expression of NEUROD, ZNFN1A3, and TOP2A that are partially inside or adjacent to the boundaries of the CTD-2019C10 clone did not correlate with the expression of any of these 8 genes. These data show a transcriptionally active oncogenomic region bounded by PPP1R1B/DARPP-32 and GRB7 in UGCs and provide further insight into expression levels of several critical genes.
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PMID:Molecular dissection of 17q12 amplicon in upper gastrointestinal adenocarcinomas. 1684 20

ERBB2 is frequently amplified in breast tumours as part of a wide region of amplification on chromosome 17q21. This amplicon contains many candidate genes for breast cancer susceptibility. We used a genetic association study design to determine if common genetic variation (frequency>or=5%) in a 400-kb region surrounding ERBB2 and containing the PPARBP, CRK7, NEUROD2, PPP1R1B, STARD3, TCAP, PNMT, CAB2, ERBB2, C17ORF37, GRB7 and ZNFN1A3 genes, was associated with breast cancer risk. Sixteen tagging single-nucleotide polymorphisms (tSNPs) selected within blocks of linkage disequilibrium from the HapMap database, one HapMap singleton SNP, and six additional SNPs randomly selected from dbSNP were genotyped using Taqman in a large study set of British women (2275 cases, 2280 controls). We observed no association between any of the genotypes or associated haplotypes and disease risk. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 90% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common variants present in our population. In summary, we found no association between common genetic variation in the 17q21 ERBB2 amplicon and breast cancer risk in British women.
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PMID:HapMap-based study of the 17q21 ERBB2 amplicon in susceptibility to breast cancer. 1711 80

We performed an integrated array comparative genomic hybridization (aCGH) and expression microarray analysis of 8 normal gastric tissues and 38 primary tumors, including 25 intestinal and 13 diffuse gastric adenocarcinomas to identify genes whose expression is deregulated in association with copy number alteration. Our aim was also to identify molecular genetic alterations that are specific to particular clinicopathological characteristics of gastric cancer. Distinct molecular genetic profiles were identified for intestinal and diffuse gastric cancers and for tumors obtained from 2 different locations of the stomach. Interestingly, the ERBB2 amplification and gains at 20q13.12-q13.33 almost exclusively discriminated intestinal cancers from the diffuse type. In addition, the 17q12-q25 gain was characteristic to cancers located in corpus and the 20q13.12-q13.13 gain was more common in the antrum. Statistical analysis was performed using integrated copy number and expression data to identify genes showing differential expression associated with a copy number alteration. Genes with the highest statistical significance included ERBB2, MUC1, GRB7, PPP1R1B and PPARBP with concomitant changes in copy number and expression. Immunohistochemical analysis of ERBB2 and MUC1 on a tissue microarray containing 78 independent gastric tissues showed statistically significant differences (p < 0.05 and <0.001) in immunopositivity in the intestinal (31 and 70%) and diffuse subtypes (14 and 41%), respectively. In conclusion, our results demonstrate that intestinal and diffuse type gastric cancers as well as cancers located in different sites of the stomach have distinct molecular profiles which may have clinical value.
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PMID:Integrated gene copy number and expression microarray analysis of gastric cancer highlights potential target genes. 1850 90

The clinical use of trastuzumab (Herceptin), a humanized antibody against the HER2 growth factor receptor, has improved survival in patients with breast tumors with ERBB2 amplification and/or over-expression. However, most patients with advanced ERBB2 amplified breast cancers whose tumors initially respond to trastuzumab develop resistance to the drug, leading to tumor progression. To identify factors responsible for acquired resistance to trastuzumab, gene expression profiling was performed on subclones of an ERBB2 amplified breast cancer cell line, BT474, which had acquired resistance to trastuzumab. The most overexpressed gene in these subclones was PPP1R1B, encoding the DARPP-32 phosphatase inhibitor. Western analysis revealed that only the truncated isoform of the DARPP-32 protein, t-Darpp, was overexpressed in the trastuzumab resistant cells. Using gene silencing experiments, we confirmed that t-Darpp over-expression was required for trastuzumab resistance in these cells. Furthermore, transfecting t-Darpp in parental BT-474 cells conferred resistance to trastuzumab, suggesting that t-Darpp expression was sufficient for trastuzumab resistance. We also found that t-Darpp over-expression was associated with Akt activation and that the T75 residue in t-Darpp was required for both Akt activation and trastuzumab resistance. Finally, we found that full-length DARPP-32 and t-Darpp are expressed in a majority of primary breast tumors. Over-expression of full-length DARPP-32 can also confer resistance to trastuzumab and, moreover, is associated with a poor prognostic value in breast cancers. Thus, t-Darpp and DARPP-32 expression are novel prognostic and predictive biomarkers in breast cancer.
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PMID:Both t-Darpp and DARPP-32 can cause resistance to trastuzumab in breast cancer cells and are frequently expressed in primary breast cancers. 1930 Nov 21

Esophageal adenocarcinoma (EAC) is an aggressive malignancy with a poor outcome. Although targeting ERBB2 with trastuzumab has been evaluated in clinical trials, the molecular mechanisms of trastuzumab resistance remain uncharacterized in EAC. The dopamine and cyclic AMP-regulated phosphoprotein of MR 32000 (DARPP-32), also known as PPP1R1B, is located together with ERBB2 at the 17q12-q21 amplicon. We evaluated the expression of a transcript variant of DARPP-32 (t-DARPP) and ERBB2 in 141 primary tumors and investigated the role of t-DARPP in trastuzumab resistance using OE19 and OE33 EAC cell models. Overexpression of t-DARPP mRNA was detected in two-thirds of tumors with a correlation between ERBB2 and t-DARPP overexpression levels (r = 0.58, P = 0.003). Cell viability and clonogenic survival assays showed that t-DARPP increased survival by 40% in response to trastuzumab (P < 0.01). The Annexin-V staining and Western blot analysis indicated that t-DARPP effectively abrogated trastuzumab-induced apoptosis, inhibited cleavage of caspase-3, and blocked trastuzumab-induced dephosphorylation of ERBB2 and AKT proteins. The knockdown of endogenous t-DARPP reversed these effects and sensitized cells to trastuzumab (P < 0.01). The cycloheximide-based protein degradation analysis indicated that t-DARPP extended the half-life of ERBB2, explaining the increase in the basal levels of ERBB2, p-ERBB2(Y1248), and p-AKT(S473). Coimmunoprecipitation and Western blot analysis showed that t-DARPP associated with ERBB2 in a protein complex, and interfered with trastuzumab binding to the ERBB2 receptor. Using EAC-xenografted mouse model, t-DARPP enhanced tumor growth and rendered tumors unresponsive to trastuzumab. This study establishes t-DARPP as a mediator of trastuzumab resistance and underscores its potential importance in clinical trials of EAC.
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PMID:Regulation of ERBB2 receptor by t-DARPP mediates trastuzumab resistance in human esophageal adenocarcinoma. 2274 69


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