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Biomedical subjects

J Yokota

Publications and source records attributed to J Yokota.

At least 19 recordsLinked to original sources
PubMed2000

Absence of hSNF5/INI1 mutation in human lung cancer.

Frequent occurrence of chromosome 22q deletions in lung cancer indicates the presence of a tumor suppressor gene on this chromosome arm. The hSNF5/INI1 gene at chromosome 22q11.2 has recently been shown to act as a tumor suppressor in rhabdoid tumors. To investigate whether the hSNF5/INI1 gene located on chromosome 22q is involved in lung carcinogenesis, mutation analysis of the hSNF5/INI1 gene was performed using 50 lung cancer cell lines. No mutations causing amino acid substitutions or frameshifts were found by PCR-SSCP analysis of the entire coding region. The results indicated that the hSNF5/INI1 gene is not inactivated in lung cancers and suggested the presence of another tumor suppressor gene on chromosome 22q. Thus, further studies are necessary to identify the target lung tumor suppressor gene(s) on chromosome 22q.

Chromosomal Proteins, Non-Histone↗
PubMed2000

Molecular cloning of a novel NF2/ERM/4.1 superfamily gene, ehm2, that is expressed in high-metastatic K1735 murine melanoma cells.

We have cloned a novel gene, Ehm2, that is expressed in high-metastatic but not in low-metastatic K-1735 murine melanoma cells. The Ehm2 gene encodes a protein of 527 amino acid residues, showing up to 41% amino acid identity with the FERM domain of NF2/ERM/4.1 superfamily proteins, which have the function of connecting cell surface transmembrane proteins to cytoskeletal molecules. The Ehm2 gene was mapped to chromosome 4 and was expressed in the liver, lung, kidney, and testis and in 7- to 17-day embryos. The highest level of homology was observed with NBL4, which is a new subfamily protein of the NF2/ERM/4.1 superfamily. A human homologue of the mouse Ehm2 gene, showing significant homology (83% identity), was identified in the genomic DNA and EST databases. Furthermore, seven rat EST clones and one pig EST clone in the GenBank EST database were identified as having 83-92% sequence homology with the cDNA sequence of the mouse Ehm2 gene. Thus, Ehm2 is a highly conserved gene that encodes a novel member of the NF2/ERM/4.1 superfamily proteins.

Animals↗
PubMed2000

Somatic mutations and genetic polymorphisms of the PPP1R3 gene in patients with several types of cancers.

Recently, we found nonsense and missense mutations of the PPP1R3 (protein phosphatase 1, regulatory subunit 3) gene in diverse human cancer cell lines and primary lung carcinomas, indicating that PPP1R3 functions as a tumor suppressor in human carcinogenesis. In this study, to assess the prevalence of PPP1R3 mutations in human primary cancers and the genetic diversity of the PPP1R3 gene in the human population, somatic mutations and genetic polymorphisms in the PPP1R3 gene were examined in 137 pairs of cancerous and non-cancerous tissues of patients with cancers of colon, ovary, and liver. Five somatic mutations including two missense mutations were detected in three cancerous tissues consisting of two colorectal carcinomas and one ovarian carcinoma. Five novel single nucleotide polymorphisms (SNPs) associated with the substitution of amino acids were also identified in cancer patients, in addition to five known nonsynonymous SNPs, including three previously reported ones as having an impact on the susceptibility to insulin resistant disorders. Differences in the activities and properties of multiple PPP1R3 proteins, which are produced in human cells due to variable somatic mutations and genetic polymorphisms in the PPP1R3 gene, can be involved in human carcinogenesis and susceptibility to diseases.

Amino Acid Substitution↗
PubMed2000

Absence of p51 mutation in human hepatocellular carcinoma.

The p51 gene encodes a protein with significant homology to p53. To investigate the involvement of the p51 gene in human hepatocarcinogenesis, mutation analysis of the p51 gene was performed in 54 cases of hepatocellular carcinoma (HCC). No mutations causing amino acid substitutions or frameshifts were found by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of the entire coding region. The result indicated that mutation of the p51 gene does not play a major role in the development of HCC in Japanese patients. Further studies on p51 expression and its functions, including the interaction with p53, are necessary to elucidate the role of the p51 gene in human hepatocarcinogenesis.

Carcinoma, Hepatocellular↗
PubMed2000

Allelic imbalance and mutations of the PTEN gene in ovarian cancer.

The PTEN/MMAC1/TEP1 tumor-suppressor gene, which maps to chromosome 10q23.3, is mutated and homozygously deleted in a variety of human tumors, including endometrioid-type ovarian tumors. We examined 33 primary ovarian cancers and 3 ovarian borderline tumors for allelic imbalance (AI) of the 10q23.3 region using 5 polymorphic markers, including an insertion/deletion-type polymorphic marker identified in intron 4 of the PTEN gene. AI at one or more loci was detected in 12 of 31 (39%) informative ovarian cancers and none of 3 ovarian borderline tumors. The commonly deleted region was mapped between the D10S215 and D10S541 loci, including the PTEN locus. Moreover, the incidence of AI at the PTEN locus (38%) was the highest among the 5 loci examined. Therefore, we searched for mutations in the entire coding region of the PTEN gene by PCR-SSCP and sequencing analyses in these tumors and 7 ovarian cancer cell lines. Mutations were detected in 3 of the 33 (9%) ovarian cancers: 2 cases with double mutations and 1 case with a mutation on 1 allele accompanied by deletions on both alleles in the poly T tract preceding the splice acceptor site in intron 7. An intragenic deletion was detected in 1 of the 7 (14%) ovarian cancer cell lines. PTEN mutations were detected not only in the endometrioid type but also in the serous and mucinous types of ovarian cancer. However, PTEN was not mutated in the 12 tumors that showed AI of the PTEN locus. Our results suggest that the PTEN gene plays an important role in the development of a subset but diverse histological types of ovarian tumors. However, it is possible that another tumor-suppressor gene in the close vicinity of the PTEN gene is also inactivated by AI of the 10q23.3 region.

Chromosome Mapping↗
PubMed2000

Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21).

The reciprocal translocation t(1;3)(p36;q21) is associated with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and a poor prognosis. As yet no molecular genetic analyses of the t(1;3) have been reported. In four patients with t(1;3), all of whom had AML-M4, which evolved from MDS, the breakpoints at 3q21 clustered within a 60-kb region centromeric to the breakpoint of the inv(3)(q21q26), whereas the breakpoints at 1p36 clustered within a 90-kb region at 1p36.3. The presence of novel clusters in both the 3q21 and 1p36 breakpoints (BCRs) suggests a common, underlying molecular mechanism for the development of t(1;3)-positive MDS/AML. The Ribophorin I (RPN1) gene close to the BCR at 3q21 was highly expressed without gross structural changes, whereas the GR6 gene located within the BCR at 3q21 was not expressed. No other highly expressed genes were isolated in a 150-kb region at 3q21. Thus, it is likely that a gene at 1p36.3 is activated by the translocation of the 3q21 region or a gene important for transformation lies on 3q21, outside the 150-kb region. Further characterization of the BCRs at 1p36.3 and 3q21 should provide important insights into the molecular genetic mechanisms involved in the genesis of t(1;3)-positive MDS/AML. Genes Chromosomes Cancer 27:229-238, 2000.

Aged↗
PubMed2000

Frequent microsatellite instability and BAX mutations in T cell acute lymphoblastic leukemia cell lines.

Allelic status of the BAT26 and BAT25 loci was examined in 117 leukemia/lymphoma cell lines consisting of 44 B-lymphoid lineage cell lines, 30 T-lymphoid cell lines and 43 myeloid cell lines to define the lineage specificity of microsatellite instability (MSI) in hematological malignancies. Seventeen (15%) cell lines were defined as having MSI. The incidence of MSI was significantly (P < 0.01) higher in cell lines of lymphoid lineage (15/74; 20%) than in those of myeloid lineage (2/43; 5%). In the cell lines of lymphoid lineage, the incidence of MSI in T cell acute lymphoblastic leukemia (T-ALL) (11/30; 37%) was significantly (P < 0.01) higher than those in B-lineage malignancies (4/44; 9%). The 17 cell lines with MSI were subjected to the mutation analysis of the coding microsatellites in 13 candidate genes. Frameshift mutations were most frequently detected in the BAX gene (14/17, 82%), while the hMSH3, hMSH6, TGFbetaRII, DRP and IGFIIR genes were less frequently mutated (24-47%). The present result indicates that MSI is involved in the development and/or progression of lymphoid malignancies, especially of T-ALL, through the inactivation of BAX and several other genes.

Gene Frequency↗
PubMed2000

Allelic imbalance on chromosome 18 in neuroblastoma.

We previously demonstrated that chromosome 18 is frequently deleted in neuroblastoma. To further elucidate the role of chromosome 18 deletions in the development of neuroblastomas we examined 82 cases of neuroblastomas for allelic imbalance (AI) at 17 loci on chromosome 18 to define the common region of AI in neuroblastoma. AI at one or more loci on chromosome 18 was detected in 18/82 (22%) cases. AI on 18q was detected in 17/82 (21%) cases, whereas AI on 18p was detected in 4/82 (5%) cases. There was a distinct common region of AI at 18q21.1 between the D18S363 and D18S858 loci. In addition, cases 16 and 53, which did not show AI at 18q21.1, showed AI at 18pter-q12.3 between the D18S52 and D18S36 loci, indicating that another common region of AI may exist on chromosome 18. AI on chromosome 18 did not significantly correlate with any clinicopathological findings of patients with neuroblastoma. The common region of AI at 18q21.1 includes the DCC gene but not the Smad2 and Smad4 genes. However, our previous studies together with the present study indicated that the incidence of DCC mutation is much less than that of AI at 18q21.1 in neuroblastoma. These results indicate that novel tumour suppressor genes involved in the development of neuroblastoma are present at 18q21.1, and possibly at 18pter-q12.3.

Blotting, Southern↗
PubMed2000

Tumor progression and metastasis.

It is now widely accepted that cancer is attributed to the accumulation of genetic alterations in cells. Thus, to understand the molecular mechanisms of cancer metastasis, it is indispensable to identify the genes whose alterations accumulate during cancer progression as well as the genes whose expression is responsible for the acquisition of metastatic potential in cancer cells. Molecular analyses of cancer cells in various stages of progression have revealed that alterations in tumor suppressor genes and oncogenes accumulate during tumor progression and correlate with the clinical aggressiveness of cancer. Comparative analyses of gene expression profiles between metastatic and non-metastatic cells have revealed that various genes are differentially expressed in association with the metastatic potential of cancer cells. A number of genes have been also identified as having functions in inducing or suppressing metastasis in experimental models. However, the association between causative genetic alterations and resulting phenotypic alterations with respect to the metastatic potential of cancer cells is not fully understood. Therefore, elucidation of genotype-phenotype correlation will be required to further understand a complex process of metastasis. Here, I review the progress on molecular studies of tumor progression and metastasis of the past 20 years and discuss the future direction in this field of science.

Animals↗
PubMed2000

A giant intracranial mucocele associated with an orbitoethmoidal osteoma. Case report.

The authors present a rare case of a giant intracranial mucocele associated with an orbitoethmoidal osteoma in a patient suffering from a generalized convulsive disorder. The broad pedicle of the osteoma had penetrated the cribriform plate and extended intracranially to form a nodular mass in the olfactory groove. The intracranial portion of the osteoma was surrounded by a mucocele. Both the cyst wall and multilayered intracystic septations of the mucocele were indented by layers of the osteoma. Although the extracranial portion adhered to the mucosa of the ethmoidal sinus, there were no signs of sinus obstruction. No direct communication other than the osteoma was identified between the mucocele and the ethmoidal mucosa. The large cerebral defect, which the mucocele occupied, communicated directly with the lateral ventricle without any intervening membranous structures. A frontal craniotomy is recommended for exposure of the lesion and plastic repair of the dural defect.

Brain Diseases↗
PubMed2000

Expression of the OGG1-type 1a (nuclear form) protein in cancerous and non-cancerous human cells.

The human OGG1 gene encodes 8-hydroxyguanine DNA glycosylase. By RT-PCR analysis, five novel type 1 transcripts, in addition to eight known types (OGG1-types 1a to 1c and 2a to 2e), were identified. Among them, only the type 1a isoform contains both a nuclear localization signal and the entire DNA binding motif, suggesting the involvement of type 1a in chromosomal DNA repair. By Western blot analysis using a monoclonal antibody prepared by immunizing the whole type 1a protein, a 39 kDa type 1a protein was detected in lung cancer cell lines and peripheral lymphocytes. The type 1a protein was expressed at a similar level, irrespective of its polymorphic types characterized by distinct repair activity. By an immunocytochemical study, the majority of type 1a protein was localized in the nucleus. These results indicate that OGG1-type 1a protein is involved in the repair of 8-hydroxyguanine in chromosomal double-stranded DNA and constitutively expressed in cancerous and non-cancerous human cells.

3T3 Cells↗
PubMed2000

Two regions of homozygous deletion clusters at chromosome band 9p21 in human lung cancer.

We examined 149 lung cancer cell lines for homozygous deletions using 24 DNA markers, which were mapped and ordered in chromosome band 9p21, to define the target regions for 9p21 deletions in human lung cancer. Homozygous deletions were detected in 39 (26%) cell lines and clustered at 2 independent regions. One was the region containing the p16/CDKN2A tumor suppressor gene, and this region was deleted in 32 (21%) cell lines. The other was the region containing D9S171, which is the locus approximately 3 Mb proximal to the CDKN2A locus. This region, designated as the D9S171 region, was deleted in 18 (12%) cell lines. Seven of the 18 cell lines had identical minimum deletions of a 17,036 bp sequence located 20 kb distal to the D9S171 locus. However, such a deletion was also observed in the corresponding B-lymphoblastoid cell line from 1 of the 7 cell lines and in 5 (16%) of 32 noncancerous tissues, suggesting that the deletion was a genetic polymorphism. By considering this polymorphism, 11 (7%) cell lines still had deletions at the D9S171 region. Two NSCLC cell lines showed deletions at the D9S171 region and retentions of the CDKN2A locus. Furthermore, an NSCLC cell line showed discontinuous deletions including either the CDKN2A or D9S171 locus. Therefore, the region surrounding the D9S171 locus was defined as another target region for the 9p21 deletions. It is possible that unknown tumor suppressor gene(s) are present in this chromosomal region. Genes Chromosomes Cancer 27:308-318, 2000.

Carcinoma, Non-Small-Cell Lung↗
PubMed1999

Identification and characterization of a new phospholipase C-like protein, PLC-L(2).

We have isolated a cDNA encoding a novel protein, PLC-L(2), with homology to the phospholipase C-like protein PLC-L and delta-type phospholipase C. PLC-L(2) contains a relatively well-conserved PH domain, PLC catalytic region, and X and Y domains. However, it did not have PLC activity. This inactivation was thought to be caused by the replacement of two amino acids that are essential for PLC activity, His356 and Tyr552, with Thr and Phe in the X and Y domain. PLC-L(2) has a wide distribution with strong expression in skeletal muscle and mapped to chromosome 3p24-25. The PH domain of PLC-L(2) bound strongly to PI(4,5)P(2) and Ins(1,4,5)P(3), and moderately to PI(4)P and PI(3,4,5)P(3). PLC-L(2) predominantly localized to perinuclear areas in both myoblast and myotube C2C12 cells. Ectopically expressed GFP-PLC-L(2) also mainly localized in perinuclear areas, including endoplasmic reticulum in COS 7 cells. Furthermore, the expression of GFP-PH showed the same intracellular distribution as the full-length PLC-L(2). All these results suggest that PLC-L(2) plays an important role in the regulation of Ins(1,4, 5)P(3) around the endoplasmic reticulum on which the Ins(1,4,5)P(3) receptor exists.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Identification of genes (SPON2 and C20orf2) differentially expressed between cancerous and noncancerous lung cells by mRNA differential display.

mRNA differential display was applied to three small cell lung carcinoma (SCLC) cell lines, six non-small cell lung carcinoma (NSCLC) cell lines, and three normal lung tissues to identify genes differentially expressed between lung carcinoma cells and normal lung tissues and between SCLC cells and NSCLC cells. We isolated five differentially expressed genes, two that were novel and three that were already known. DIL-1 (differentially expressed in cancerous and noncancerous lung cells; HGMW-approved symbol SPON2) and pulmonary surfactant apoprotein A were expressed in normal lung tissues but not in lung carcinoma cell lines, whereas DIL-2 (HGMW-approved symbol C20orf2) and nm23-H1 were expressed in lung carcinoma cell lines but not in normal lung tissues. The remaining gene, Annexin II, was expressed at a lower level in SCLC than in NSCLC and normal lung tissues. These genes were also differentially expressed in primary lung cancers. One of the two novel genes, DIL-1, encodes a secreted protein homologous to the Mindin/F-spondin family. The other, DIL-2, encodes a protein with a putative ATP/GTP binding site motif. These data provide basic information necessary to understand the differences in gene expression profiles between lung carcinoma and normal lung and between SCLC and NSCLC. Further characterization of these genes will help to clarify the molecular mechanisms of human lung carcinogenesis.

Amino Acid Sequence↗
PubMed1999

Alterations of the PPP1R3 gene in human cancer.

Recently, the PTEN/MMAC1 gene encoding a protein phosphatase (PP) and the PPP2R1B gene encoding a regulatory subunit of PP2A have been identified as being genetically altered in several types of human cancers, indicating that aberrations of intracellular signaling pathways via PPs are involved in human carcinogenesis. Here we report genetic alterations of the PPP1R3 gene located at chromosome 7q31, which encodes regulatory subunit 3 of PP1, in various types of human cancers. Mutations of the PPP1R3 gene were detected in 5 of 33 (15%) non-small cell lung cancer cell lines and 2 of 38 (5%) primary non-small cell lung cancers and were also observed in cell lines derived from a small cell lung cancer, an ovarian cancer, a colorectal cancer, and a gastric cancer. Mutations were widely dispersed in the coding region of the PPP1R3 gene. Three of the 11 detected mutations were nonsense mutations, whereas the remaining ones were missense mutations, most of which caused substitutions of evolutionarily conserved amino acids. These findings suggest that PPP1R3 alteration plays a role in the development of human cancers and that PPP1R3 could act as a tumor suppressor gene.

Amino Acid Sequence↗
PubMed1999

CYP2A6 gene deletion reduces susceptibility to lung cancer.

CYP2A6 is an enzyme with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogen. In the present study, we investigated the relationship between genetic polymorphism of CYP2A6 and lung cancer risk in a case-control study of Japanese subjects. Genotyping of the CYP2A6 gene in both healthy volunteers and lung cancer patients was conducted. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion-type mutation (deletion), which causes lack of the enzyme activity, was lower in the lung cancer patients than in the healthy control subjects. The odds ratio (OR) of the group homozygous for the deletion was significantly lower and calculated to be 0.25 (95% CI; 0.08-0.83) when the OR for the population with homozygotes of the CYP2A6 wild-type gene was defined as 1.00. In the allelic-base analysis, there was also a significant decrease in the OR for the deletion allele. These data suggest that deficient CYP2A6 activity due to genetic polymorphism reduces lung cancer risk.

Aged↗
PubMed1999

The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein.

Autocrine motility factor receptor (AMFR) is a cell surface glycoprotein of molecular weight 78,000 (gp78), mediating cell motility signaling in vitro and metastasis in vivo. Here, we cloned the full-length cDNAs for both human and mouse AMFR genes. Both genes encode a protein of 643 amino acids containing a seven transmembrane domain, a RING-H2 motif and a leucine zipper motif and showed a 94.7% amino acid sequence identity to each other. Analysis of the amino acid sequence of AMFR with protein databases revealed no significant homology with all known seven transmembrane proteins, but a significant structural similarity to a hypothetical protein of Caenorhabditis elegans, F26E4.11. Thus, AMFR is a highly conserved gene which encodes a novel type of seven transmembrane protein.

Amino Acid Sequence↗