Biomedical subjects

Mitsuru Emi

Publications and source records attributed to Mitsuru Emi.

At least 55 records · Page 3Linked to original sources

PubMed2003

Association of a promoter haplotype (-1542G/-525C) in the tumor necrosis factor receptor associated factor-interacting protein gene with low bone mineral density in Japanese women.

Osteoporosis, a multifactorial common disease, is believed to result from the interplay of multiple environmental and genetic factors that regulate bone mineral density (BMD). Tumor necrosis factor receptor associated factor-interacting protein (I-TRAF) is an essential effecter of the tumor necrosis factor receptor-signaling cascade, one of the most potent bone-resorbing systems. In genetic studies of 382 Japanese adult women, we found that genotypes of two promoter variations of I-TRAF gene, -1542T/G and -525G/C, were similarly associated with radial BMD levels. Two variations were in almost complete linkage disequilibrium (D' = 0.978, r(2) = 0.917, chi(2) = 695, 2, P = 3.4 x 10(-153)), and there were two exclusive haplotypes (-1542T/-525C, frequency 0.74, and -1542G/-525G, frequency 0.24) among our test subjects. When BMD values were compared among the three haplotypic categories (-1542G/-525G homozygotes, heterozygotes, and -1542T/-525C homozygotes), BMD was lowest among -1542G/-525C homozygotes (mean +/- SD = 0.382 +/- 0.060 g/cm(2)), highest among -1542T/-525G homozygotes (0.405 +/- 0.051 g/cm(2)), and intermediate among heterozygotes (0.395 +/- 0.056 g/cm(2)) (r = 0.11, P = 0.030). The observed trend supported a codominant effect of the relevant haplotype of I-TRAF gene in determination of radial BMD. These results suggested that variation of I-TRAF might be an important determinant for postmenopausal osteoporosis.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Amplification, up-regulation and over-expression of DVL-1, the human counterpart of the Drosophila disheveled gene, in primary breast cancers.

Wnt proteins form a family of highly conserved, secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Wnt genes and Wnt signaling are also implicated in cancer. It has been shown that Wnt proteins bind to receptors of the frizzled family on the cell surface. Through several cytoplasmic relay components including DVL-1, the human counterpart of the Drosophila disheveled gene, the signal is transduced to beta-catenin, which then enters the nucleus and forms a complex with T-cell factor (TCF) to activate transcription of Wnt target genes. We describe here the amplification of DVL-1 in 13 of 24 primary breast cancers examined, and increased expression of this gene in 11 of those tumors in comparison to corresponding non-cancerous breast tissues. Immunohistochemical staining demonstrated that DVL-1 protein was prominent in the cytoplasm of cancer cells, but not in normal epithelial cells of the mammary duct or in myoepithelial cells. These data indicate that amplification and increased expression of the DVL-1 gene may play some role in human breast carcinogenesis through derangement of the Wnt signaling pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma.

A number of genetic events have been reported in prostate carcinogenesis, including frequent loss of heterozygosity (LOH) on chromosomes 8q, 10q, 16q and 18q. In samples of heterogeneous, multifocal prostate carcinomas, we focused on chromosome 6q using PCR-based techniques with 15 microsatellite markers to identify the specific 6q deletion within tumors. LOH of one or more polymorphic markers was detected in 10 of 21 tumors (48%). Two of these 10 tumors demonstrated LOH in all cancerous foci at specific loci and 4 tumors showed deletion in one focus. Different deletion patterns were found in 3 tumors when different polymorphic markers were used. In 90% of tumors showing LOH in one or more foci, however, two common regions of LOH were identified; one at 1.81 cM on 6q15-16.3 between markers D6S1631 and D6S1056, and the other at 5.11 cM on 6q16-21 between markers D6S424 and D6S283. By RT-PCR analysis, the TAK1 gene located at these loci did not correlate with LOH status, indicating that TAK1 is not a target gene in prostate carcinoma. The 6q deletion occurs heterogeneously and LOH was more frequent in tumors of higher pathological stages, implying that this alteration is a late event in prostate carcinogenesis. Because prostate carcinomas are genetically multicentric and of multifocal origin, it remains unclear whether the foci containing 6q deletions specifically expand within tumors or to what extent they contribute to the histological heterogeneity characteristic of the disease.

Aged↗

PubMed2003

Association of a haplotype (196Phe/532Ser) in the interleukin-1-receptor-associated kinase (IRAK1) gene with low radial bone mineral density in two independent populations.

Osteoporosis, a multifactorial common disease, is believed to result from the interplay of multiple environmental and genetic determinants, including factors that regulate bone mineral density. Interleukin-1 (IL-1) is one of the most potent bone-resorbing factors, and interleukin-1-associated kinase 1 (IRAK1) is an essential effector of the IL-1 receptor signaling cascade. In genetic studies of two independent populations of postmenopausal women (cohort A: 220 individuals and cohort T: 126 individuals) from separated geographical regions of Japan, we found that radial bone mineral density levels had similar associations with IRAK1 genotypes in both populations. Two amino acid-substituting variations in the gene, encoding Phe196Ser and Ser532Leu, were in complete linkage disequilibrium (D' = 1.0000, r2 = 1.0000, chi2 = 192.000, p = 1.2 x 10(-43)), and we found two exclusive haplotypes (196F/532S, frequency 0.74; 196S/532L, frequency 0.26) of the IRAK1 gene among our test subjects. In both populations, a significant association with decreased radial bone mineral density was identified with haplotype 196F/532S (in cohort A: r = 0.21, p = 0.0017; in cohort T: r = 0.23, p = 0.011). Radial bone mineral density was lowest among 196F/532S homozygotes, highest among 196S/532L homozygotes, and intermediate among heterozygotes. Accelerated bone loss also correlated with the 196F/532S haplotype in a 5-year follow-up. These results suggest that variation of IRAK1 may be an important determinant of postmenopausal osteoporosis, in part through the mechanism of accelerated postmenopausal bone loss.

Base Sequence↗

PubMed2003

Association of molecular variants, haplotypes, and linkage disequilibrium within the human vitamin D-binding protein (DBP) gene with postmenopausal bone mineral density.

UNLABELLED: Possible contribution of vitamin D-binding protein (DBP) gene for determination of BMD was tested by characterizing 13 SNPs in 384 adult Japanese women. When the effect of a specific single SNP was tested, five SNPs (-39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) correlated with BMD significantly at various levels. The chromosomal dosage of one haplotype (T-C-C-G-T-C in -39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E, and IVS11+1097G>C) displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Multiple regression analyses revealed a most significant correlation with the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis. INTRODUCTION: Osteoporosis results from the interplay of multiple environmental and genetic determinants. The gene encoding vitamin D-binding protein (DBP), a key factor for regulating calcium homeostasis through the vitamin D endocrine system, is a probable candidate for conferring susceptibility to osteoporosis. METHODS: To test a possible contribution of the DBP gene for determination of bone mineral density (BMD) of adult women, we have characterized 13 single nucleotide polymorphisms (SNPs) within the DBP gene in DNA from 384 adult Japanese women and attempted to correlate specific SNPs with BMD. RESULTS AND CONCLUSIONS: Sixteen major haplotypes accounted for 80% of the variations, indicating allelic complexity in this genomic region. Pairwise linkage disequilibrium (LD), measured by the D' and r2 statistics, demonstrated a general pattern of decline with increasing distance, but individual LD values within small genomic segments were diverse. Regression analysis for adjusted BMD revealed significant correlation with respect to five of them (-39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) at various levels. An intronic SNP (IVS11+1097G>C) with the highest significance of association (p = 0.006) showed significant LD with four SNPs located around the first exon (r2 values > 0.18, D' > 0.5). A non-synonymous coding SNP, D432E, showed a comparable level of correlation, but it was in a moderate LD only with IVS11+1097G>C. The chromosomal dosage of one haplotype (T-C-C-G-T-C in -39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E and IVS11+1097G>C) estimated in each subject displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Furthermore, multiple regression analyses revealed that the most significant correlation was achieved for the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis.

Aged↗

PubMed2003

Apolipoprotein H variant modifies plasma triglyceride phenotype in familial hypercholesterolemia: a molecular study in an eight-generation hyperlipidemic family.

In the course of investigating familial coronary artery disease in Utah, we studied 196 members of an eight-generation extended family of familial hypercholesterolemia (FH), in which 73 members were affected with type IIa hyperlipoproteinemia (HLPIIa; high plasma cholesterol) and 11 members with type IIb hyperlipoproteinemia (HLPIIb; high plasma cholesterol as well as plasma triglyceride). A splice-site mutation of the LDL receptor (LDLR) gene (IVS14 + G > A) co-segregated with elevated plasma cholesterol among all the members, but not with the elevated plasma triglyceride and VLDL cholesterol levels seen in HLPIIb patients. The apolipoprotein H (apoH) gene plays a role in plasma triglyceride removal and lipoprotein lipase enhancement. Intra-familial correlation analysis of the modifier effect of Val247Leu substitution in the apoH gene was carried out among 84 LDLR-mutation carriers and 112 non-carriers. When plasma triglyceride levels in the LDLR-mutation carriers were compared, the values were lowest among V/V homozygotes (mean +/- SD = 145 +/- 53 mg/dl), highest in L/L homozygotes (277 +/- 177 mg/dl), and intermediate among V/L heterozygotes (191 +/- 102 mg/dl) (p = 0.0015). All eleven patients who presented with HLPIIb had inherited both the defective LDLR allele and an apoH 247Leu allele, whereas all 45 carriers of the defective LDLR allele not carrying the apoH Leu allele presented with HLPIIa but not HLPIIb (p = 0.0001). These results indicate a significant modification of the phenotype of FH with a defective LDLR allele, by apoH Leu variation in our studied family.

Adolescent↗

PubMed2002

Combined hypermethylation and chromosome loss associated with inactivation of SSI-1/SOCS-1/JAB gene in human hepatocellular carcinomas.

We previously demonstrated using restriction landmark genomic scanning-based 2-dimensional genome electrophoresis method decreased results of 16 primary hepatocellular carcinomas (HCCs) revealed reduction of intensity of 60 NotI-landmark spots, and increase in five spots that were frequently observed in HCCs. Most frequently decreased spot (14/16 HCCs) was identified to it corresponds to a gene encoding SSI-1, a JAK-binding protein (SSI-1/SOCS-1/JAB) that regulated the JAK/STAT signal transduction pathway. This signaling pathway is important for relaying signals from various cytokines outside the cell to the inside. Expression level of SOCS-1 messenger RNA was markedly suppressed in 50% of HCCs (4/8). Loss of heterozygosity at the SSI-1 gene, was found in all cases with aberrant expression. Methylation analysis of the CpG-rich regions of SSI-1 gene revealed hypermethylation of these regions. In an additional series of methylation analysis using 30 HCCs, 16 (53%) showed hypermethylation of the gene. These results indicate that the SSI-1 gene is silenced in a substantial portion of HCC though the combined mechanisms of methylation of either 5' or exon CpG rich regions and by a chromosomal loss of the remaining allele.

Carcinoma, Hepatocellular↗

PubMed2002

Universal fluorescent labeling (UFL) method for automated microsatellite analysis.

We have devised a novel method for automated microsatellite analysis using "universal" fluorescent labeling. This system is based on polymerase chain reactions driven by sequence-specific primers and a reporter primer labeled with a fluorescent dye at its 5' end. The forward sequence-specific primer is designed with a tag region bearing no homology to any human genomic sequence. Complementary tag sequences act as templates for the 6-carboxyfluorescein-labeled reporter primer, and those products can be analyzed with an autosequencer. The results we achieved with this assay system were consistent with the results of conventional assays using radioisotope-labeled primers, and diagnosis required less time. Furthermore, the fluorescent-labeled reporter primer is "universal" in that it can be used with different sequence-specific primers designed to carry the appropriate tag sequence at their 5'-ends. Our observations suggest that the "universal" fluorescent labeling method is an efficient tool for analyzing sequence variations in human DNA.

DNA Primers↗

PubMed2002

Down-regulation of a novel gene, DRLM, in human liver malignancy from 4q22 that encodes a NAP-like protein.

Frequent observations of allelic loss in chromosomal band 4q21-22 in hepatocellular carcinoma (HCC) have suggested the presence of one or more tumor suppressor genes in this region. We screened HCC cell lines by reverse transcription-polymerase chain reaction (RT-PCR) to detect alterations in expression of genes within the region in question by examining expressed sequence tags located there. These experiments identified a full-length cDNA of 2311 bp in length encoding a novel, 182-amino-acid peptide belonging to the class of nucleosome assemble protein lacking nuclear localization signal sequence. Polyclonal antibody was raised by expression of a constructed recombinant glutathione S-transferase fusion protein. in vitro expression and Western blotting revealed that the novel protein distributed in cytoplasm. This gene showed loss or extreme decrease of expression in five of 13 HCC cell lines. We named it DRLM ('down-regulated in liver malignancy'). Our results suggest that loss of expression of DRLM at 4q21-22 may play an important role in human hepatocarcinogenesis.

3T3 Cells↗

PubMed2002

Association of allelic loss at 8p22 with poor prognosis among breast cancer cases treated with high-dose adjuvant chemotherapy.

To identify specific allelic losses that might correlate with postoperative mortality of breast cancer patients treated with high-dose adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and fluorouracil, we examined tumors from a cohort of 150 such patients, who were followed clinically for 5 years postoperatively, for allelic losses (loss of heterozygosity, LOH) among 18 microsatellite markers throughout the genome. Patients whose tumors had lost an allele at 8p22 had significantly higher risks of mortality than those whose tumors retained both alleles at those loci. At 8p22, the 5-year mortality rate was 31% among patients with losses vs. 8% with retention (P=0.0354). No other region showed correlation between LOH and prognosis. The data indicate that LOH at 8p22 is a significant predictor of postoperative mortality for breast cancer patients who received high-dose postoperative adjuvant chemotherapy. Thus, LOH at 8p22 can serve as a negative prognostic indicator to guide postoperative management of patients.

Adult↗

PubMed2002

Accuracy of genotyping for single nucleotide polymorphisms by a microarray-based single nucleotide polymorphism typing method involving hybridization of short allele-specific oligonucleotides.

Advances in technologies for identifying genetic polymorphisms rapidly and accurately will dramatically accelerate the discovery of disease-related genes. Among a variety of newly described methods for rapid typing of single-nucleotide polymorphisms (SNPs), gene detection using DNA microarrays is gradually achieving widespread use. This method involves the use of short (11- to 13-mer) allele-specific oligonucleotides. This method allows simultaneous analysis of many SNPs in DNAs from a large number of individuals, in a single experiment. In this work, we evaluated the accuracy of a new microarray-based short allele-specific oligonucleotide (ASO) hybridization method. There is a 96-well formatted array on a single plate, in which up to 256 spots are included in each well. Fluorescent probes for our experiments were produced by multiplex PCR amplification often target SNP-containing regions. We genotyped 192 individuals across a panel of ten single base variations, which included an insertion/deletion polymorphism. For comparison, we genotyped the same individuals for the same SNPs by the method of single-base extension with fluorescence detection. The typing accuracies of the microarray-based PCR-ASO and single-base extension methods were calculated as 99.9% and 99.1%, respectively, on the basis of genotyping results determined by direct sequencing. We conclude that the microarray-based hybridization method using short ASO probes represents a potential breakthrough technology for typing large numbers of SNPs rapidly and efficiently.

Alleles↗

PubMed2002

Genomic structure of the human NLK (nemo-like kinase) gene and analysis of its promoter region.

Recent search revealed that nemo-like kinase (NLK) was identified as a negative regulator of the wingless type signal cascade in Xenopus and in Caenorhabditis elegans. NLK phosphorylates T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) and interferes with binding of the beta-catenin-TCF/LEF complex to its TCF target site. After we constructed bacterial artificial chromosome clone contig covering more than 45-kb NLK chromosomal gene, genomic cloning revealed that the human NLK gene consists of 11 exons interrupted by ten introns; its translation-initiation site is within exon 1, and the termination codon and polyadenylation signal lie in exon 11. The 289 amino acids of its kinase domain extend from the 3'-portion of exon 1 to the 5'-portion of exon 9, and show a high degree of similarity in amino acid sequence to kinase domains of extracellular-signal regulated kinase 5 (mitogen activated protein kinase 7) and cyclin-dependent kinases, although the positions of introns among those genes are not conserved. Reverse transcription polymerase chain reactions analysis in various tissues showed that NLK is expressed ubiquitously. Analysis of its promoter region by luciferase reporter assays in transfected HeLa and NIH3T3 cells revealed that an upstream region from -487 to +33 bp of the NLK gene contains significant promoter activity. This 5'-flanking region probably contains the cis-acting element of NLK. In addition, our mutation screening showed that NLK was not a mutational target in breast and colorectal tumor cells.

3T3 Cells↗

PubMed2002

Differential expression of multiple isoforms of the ELKS mRNAs involved in a papillary thyroid carcinoma.

A novel gene, ELKS, whose 5' portion was fused to the RET gene, was found in a papillary thyroid carcinoma. A cDNA of this gene obtained from a human-brain cDNA library revealed that it encoded a peptide of 948 amino acids, termed ELKSalpha. We identified four other isoforms, which encoded ELKSbeta, ELKSgamma, ELKSdelta, and ELKSepsilon proteins consisting, respectively, of 992, 720, 1088, and 1116 amino acid residues. Analysis of the gene structure revealed that the isoforms were generated by alternative splicing. Isoforms beta, gamma, delta, and epsilon all contain an optional exon (exon14a), but ELKSgamma, -delta, and -epsilon lack exon 1b. ELKSgamma lacks exons 3 to 6. ELKSdelta and -epsilon lack exons 12 and 17; ELKSepsilon contains an optional exon (exon 6a). Analysis by RT-PCR suggested that ELKSalpha and ELKSbeta mRNAs are abundant in the brain, ELKSdelta and ELKSepsilon mRNAs predominate in testis and thyroid, and ELKSepsilon mRNA predominates in other tissues. To prove whether the fusion of different ELKS isoforms to RET (between ELKS coiled-coil domains and the RET kinase domain) could produce chimeric proteins that could be autophosphorylated, we synthesized ELKSgamma-RET, ELKSdelta-RET, and ELKSepsilon-RET fusion proteins in vitro. Immunoblotting with anti-ELKS, anti-RET, and anti-phosphotyrosine antibodies demonstrated that the chimeric proteins were constitutively phosphorylated at tyrosine residues, whereas native RET protein was not. These results indicate that the ELKS gene is alternatively spliced, and that every type of ELKS-RET chimeric protein having oligomerization domains can activate RET's cytoplasmic tyrosine kinase.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Correlation of allelic losses and clinicopathological factors in 504 primary breast cancers.

BACKGROUND: We have defined 18 chromosomal regions in which allelic losses were frequent among breast cancers. We examined whether specific allelic losses might correlate with any clinicopathological factors. METHODS: We tested DNA from matched normal and tumor tissues for loss of heterozygosity (LOH) at 18 microsatellite loci from a cohort of 504 patients who had undergone surgery for breast cancer. RESULTS: LOH at 3p14.3 correlated with a larger size of tumor (greater than 2 cm). LOH at 1p22, 3p25.1, 3p14.3, or 17q21.1 correlated with loss of estrogen receptors. LOH at as many as eleven regions correlated with loss of progesterone receptor, suggesting that these represent general phenomena associated with progression of cancer. Above all, allelic losses at 11q23-24, 13q12, 17p13.3, or 22q13 significantly correlated with lymph-node metastasis (11q23-24, p= 0.0042; 13q12, p=0.0207; 17p13.3, p=0.0478; 22q13, p=0.0162). CONCLUSION: These results suggest that some clinical characteristics of breast cancers are determined by loss of tumor suppressor genes present at specific chromosome regions. Especially, LOH at 11q23-24, 13q12, 17p13.3, and 22q13 is a significant predictor of lymph-node metastasis for patients who have undergone surgery for breast cancer, and may serve as a negative prognostic indicator.

Adult↗

PubMed2002

Eight novel mutations and functional impairments of the LDL receptor in familial hypercholesterolemia in the north of Japan.

In the course of investigations of familial coronary artery disease in Hokkaido, the northland of Japan, we identified 13 families affected by familial hypercholesterolemia. Among them, we identified eight novel mutations of the low-density lipoprotein (LDL) receptor gene, four of which caused frameshifts: (1) a 7-bp deletion at nucleotide (nt) 578-584 (codon 172-174, exon 4); (2) a 14-bp insertion at 682nt (codon 207-208, exon 4); (3) a 49-bp deletion at nt 943-991 (codon 294-310, exon 7); and (4) a one-base insertion of C to a stretch of C3 at nucleotides 1687-1689 or codon 542. The others included (5) a T-to-C transition at nt 1072 causing substitution of Cys for Arg at codon 337 (C337R, exon 8); (6) a splice-site G-to-T substitution in intron 11; (7) a splice-site G-to-C substitution in intron 11; and (8) a G-to-T transition at nt 1731 causing substitution of Trp for Cys at codon 556 (W556C, exon 12). To disclose the functional consequences of novel mutations, we characterized each of these mutations by two assays in peripheral lymphocytes, i.e., uptake of fluorescently labeled LDL by LDL receptors, and measurement of cell surface-bound LDL receptor protein using specific monoclonal antibody against LDL receptor.

Adult↗

PubMed2002

Genomic structure and eight novel exonic polymorphisms of the human N-cadherin gene.

Analysis of the detailed genomic structure of human N-cadherin revealed that the 16-exon gene is more than 72 kb in length and that it consists of a mosaic of exons. Five repeated cadherin domains, a transmembrane domain, and a cytoplasmic domain are encoded by exons 4 to 13, 13 and 14, and 14 to 16, respectively. A search for molecular variants in the entire coding region in 96 Japanese individuals resulted in the identification of eight sequence polymorphisms including three CCT- or GCC-type trinucleotide repeat polymorphisms adjacent to the initiation codon and five other novel single-nucleoticle polymorphisms (SNPs) in the coding region. Three of the five SNPs accompanied an amino acid substitution: Ala118Thr, Ala826Thr, and Asn845Ser. Knowlege of the fine gene structure and eight novel polymorphisms will be useful for the genetic study of the role of N-cadherin in diseases involving cell adhesion in the brain and in cardiomyocytes.

Brain Neoplasms↗

PubMed2002

Clinical variant of Tangier disease in Japan: mutation of the ABCA1 gene in hypoalphalipoproteinemia with corneal lipidosis.

Despite progress in molecular characterization, specific diagnoses of disorders belonging to a group of inherited hypoalphalipoproteinemias, i.e., apolipoprotein AI deficiency, lecithin-cholesterol acyltransferase deficiency, Tangier disease (TD), and familial high-density lipoprotein (HDL) deficiency, remain difficult on a purely clinical basis. Several TD patients were recently found to be homozygous for mutations in the ABCA1 gene. We have documented here a clinical variant of TD in a Japanese patient who manifested corneal lipidosis and premature coronary artery disease as well as an almost complete absence of HDL-cholesterol, by identifying a novel homozygous ABCA1 mutation (R1680W). We propose that patients with apparently isolated HDL deficiency who are found to carry ABCA1 mutations may in fact belong to a category of TD patients whose phenotypic features are only partially expressed, and that a number of hidden clinical variants of TD might exist among other HDL deficiency patients who have escaped correct clinical diagnosis.

ATP Binding Cassette Transporter 1↗

PubMed2002

Head-to-head juxtaposition of Fas-associated phosphatase-1 (FAP-1) and c-Jun NH2-terminal kinase 3 (JNK3) genes: genomic structure and seven polymorphisms of the FAP-1 gene.

When characterizing the 5' flanking region of the c-Jun NH2-terminal kinase 3 ( JNK3) gene at 4q21-22, where frequent allelic losses and loss of expression had been detected in patients with brain tumors and hepatocellular carcinomas, we discovered that the Fas-associated phosphatase-1 ( FAP-1) gene was located only 633 bp upstream from JNK3 in a head-to-head orientation. A short G/C-rich region between the cap sites of the two genes suggested that they might share a bidirectional promoter region that appeared to contain multiple cis elements, including Sp1, AP-1, AP-2, GATA-1, a GC box, and a CCAAT box. The FAP-1 gene, consisting of 48 exons, initiates transcription within exon 2 and terminates in exon 48. Exons 2-5, 21-23, 25-28, 29-30, 33-34, and 34-36 encode six Gly-Leu-Gly-Phe repeat domains, and exons 12-17 and 44-88 encode the membrane-binding and catalytic domains, respectively. Seven polymorphisms were identified within functional domains or the putative promoter region, including two with amino acid substitutions, Leu1419Pro and Ile1522Met.

Base Sequence↗