Details of a Researcher - TOKINO Takashi

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No evidence of mutation in the human PTC gene, responsible for nevoid basal cell carcinoma syndrome, in human primary squamous cell carcinomas of the esophagus and lung

K Suzuki, Y Daigo, S Fukuda, T Tokino, M Isomura, K Isono, B Wainwright, Y Nakamura

JAPANESE JOURNAL OF CANCER RESEARCH ( ELSEVIER SCI IRELAND LTD ) 88 ( 3 ) 225 - 228 1997.03

The high frequency of loss of heterozygosity that has been observed on the distal region of the long arm of chromosome 9 in squamous cell carcinomas of esophagus, lung, uterus, and head and neck indicates the presence of a tumor suppressor gene(s) in this region. To investigate the possible role of the PTC gene on chromosome 9q22.3, that was identified as the cause of nevoid basal cell carcinoma syndrome, during carcinogenesis in esophagus and lung, we examined 20 esophageal squamous cell carcinomas and 10 squamous cell carcinomas of the lung for mutations in any coding exon of PTC. Using single-strand conformation polymorphism and direct sequencing, we detected no mutations other than two non-deleterious polymorphisms. Our results suggest that inactivation of some tumor suppressor gene(s) on 9q other than PTC contributes to the development of squamous cell carcinomas in these tissues.

Mutational analysis of the hMLH1 gene using an automated two-dimensional DNA typing system

S Sasaki, T Tokino, T Miyatsu, T Muto, Y Nakamura

HUMAN MUTATION ( WILEY-LISS ) 9 ( 2 ) 164 - 171 1997

Searching for mutations in DNA mismatch repair genes is important not only for presymptomatic diagnosis, but also for documenting the spectrum of mutations among families carrying predispositions to hereditary nonpolyposis colorectal cancer (HNPCC). We utilized an automated two-dimensional DNA typing system for mutational analysis of the hMLH1 gene and established optimal conditions for application of the technique to analysis of hMLH1. This approach enabled us to visualize 21 spots covering all 19 coding exons on a single gel and to envisage whether and where: any mutations existed. All mutations that we had detected previously by other means in a panel of HNPCC patients and in one patient with sporadic endometrial cancer were also detectable by this method. Furthermore, using the 2-D system, we screened the entire coding regions of the hMLH1 gene in DNAs isolated from affected individuals belonging to two large HNPCC kindreds and four HNPCC-like kindreds, and from four patients with multiple primary cancers as well as eight sporadic colorectal cancers with replication error (RER)-positive phenotypes. We detected novel germline mutations in one HNPCC proband and one sporadic colorectal cancer with the RER-positive phenotype and one polymorphism in two HNPCC-like kindreds. This new diagnostic method is applicable to mutation of analysis of any disease causing gene, and it offers a major improvement over current approaches. (C) 1997 Wiley-Liss, Inc.

DOI

Cloning and characterization of BAI2 and BAI3, novel genes homologous to brain-specific angiogenesis inhibitor 1 (BAI1)

T Shiratsuchi, H Nishimori, H Ichise, Y Nakamura, T Tokino

CYTOGENETICS AND CELL GENETICS ( KARGER ) 79 ( 1-2 ) 103 - 108 1997

We have identified two novel human genes homologous to BAI1 (brain-specific angiogenesis inhibitor 1), an angiogenesis inhibitor that is a candidate for involvement in development of glioblastoma. Like BAI1, these two genes, designated BAI2 and BAI3, were specifically expressed in brain, and are likely to be expressed in the same type of cells. However, in spite of similar tissue specificity among the three BAI genes, only BAI1 is transcriptionally regulated by p53. BAI3 expression was absent in two of nine glioblastoma cell lines examined and was significantly reduced in three of the remaining seven. These data suggest that members of this novel gene family may play important roles in suppression of glioblastoma. BAI1, BAI2 and BAI3 were mapped to 8q24, 1p35 and 6q12, respectively.

Isolation of a novel GPI-anchored gene specifically regulated by p53; Correlation between its expression and anti-cancer drug sensitivity

T Furuhata, T Tokino, T Urano, Y Nakamura

ONCOGENE ( STOCKTON PRESS ) 13 ( 9 ) 1965 - 1970 1996.11

We have identified a novel gene inducible by wild-type p53. A significant correlation between expression of this gene and p53 status in cells derived from esophageal cancers indicated that this gene is likely to be specifically regulated in a p53-dependent manner. As the predicted amino acid sequence showed a high degree of homology to the family of glycosyl-phosphatidylinositol (GPI)-anchored membrane proteins, we termed this gene GML (GPI-anchored molecule-like protein). Introduction of GML cDNA suppressed the growth of esophageal cancer cells in culture. A correlation between the presence of GML expression and the sensitivity of esophageal cancer cells to anti-cancer drugs implied that the gene product plays a significant role in the apoptotic pathway or cell-cycle regulation induced by p53 after DNA damage.

Cooperation of the tumour suppressors IRF-1 and p53 in response to DNA damage

N Tanaka, M Ishihara, MS Lamphier, H Nozawa, T Matsuyama, TW Mak, S Aizawa, Takashi Tokino, M Oren, T Taniguchi

NATURE ( MACMILLAN MAGAZINES LTD ) 382 ( 6594 ) 816 - 818 1996.08

NORMALLY growing cells promptly cease DNA synthesis when exposed to genotoxic stresses, such as radiation, and this cell-cycle arrest prevents the accumulation of mutations(1,2). The transcription factor interferon regulatory factor (IRF)-1 is essential for the regulation of the interferon system(3-5), inhibits cell growth, and manifests tumour-suppressor activities(6,7). Here we show that mouse embryonic fibroblasts (EFs) lacking LRF-1 are deficient in their ability to undergo DNA-damage-induced cell-cycle arrest. A similar phenotype has been observed in EFs lacking the tumour suppressor p53 (refs 8, 9), although the expression of IRF-1 and p53 are independent of one another. Furthermore, we show that transcriptional induction of the gene encoding p21 (WAF1, CIP1)(10-12), a cell-cycle inhibitor, by gamma-irradiation is dependent on both p53 and IRF-1, and that the p21 promoter is activated, either directly or indirectly, by both in a transient cotransfection assay. These two tumour-suppressor transcription factors therefore converge functionally to regulate the cell cycle through the activation of a common target genes.

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Characterization of the human p57(KIP2) gene: Alternative splicing, insertion deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis

Takashi Tokino, T Urano, T Furuhata, M Matsushima, T Miyatsu, S Sasaki, Y Nakamura

HUMAN GENETICS ( SPRINGER VERLAG ) 97 ( 5 ) 625 - 631 1996.05

We have isolated human cDNA and genomic clones of a gene termed p57(KIP2), which is related to the p21(WAF1) and p27(KIP1) genes that encode inducible inhibitors of cyclin-dependent kinase activity. The p57 gene contains three GC-rich introns of 166 bp, 566 bp, and 83 bp, and two of the four exons correspond to coding regions. Alternative splicing generates the heterogeneity in the translational initiations. As this gene has been localized to chromosomal band 11p15.5, a region thought to be the location of a tumor suppressor gene(s) for carcinomas of the breast, bladder, and liver, we have examined a large number of tumors for genetic alterations of p57. Although no somatic mutation has been detected, we have found several normal variations in this gene, including four types of 12-bp in-frame deletions in the proline/alanine repeating domain, in which nearly 40 motifs, viz., 5'CCGGCC-3', are tandemly repeated.

DOI PubMed CiNii

Definition of the locus responsible for systemic carnitine deficiency within a 1.6-cM region of mouse chromosome 11 by detailed linkage analysis

K Okita, T Tokino, H Nishimori, K Miura, H Nikaido, J Hayakawa, A Ono, M Kuwajima, Y Matsuzawa, Y Nakamura

GENOMICS ( ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS ) 33 ( 2 ) 289 - 291 1996.04

Carnitine is an essential cofactor for oxidation of mitochondrial fatty acids. Carnitine deficiency results in failure of energy production by mitochondria and leads to metabolic encephalopathy, lipid-storage myopathy, and cardiomyopathy. The juvenile visceral steatosis (JVS) mouse, an animal model of systemic carnitine deficiency, inherits the JVS phenotype in autosomal recessive fashion, through a mutant allele mapped to mouse chromosome 11. As a step toward identifying the gene responsible for JVS by positional cloning, we attempted to refine the jvs locus in the mouse by detailed linkage analysis with 13 microsatellite markers, using 190 backcross progeny. Among the 13 loci tested, 5 (defined by markers D11Mit24, D11Mit111, D11Nds9, D11Mit86, and D11Mit23) showed no recombination, with a maximum lod score of 52.38, Our results implied that the jvs gene can be sought on mouse chromosome 11 within a genetic distance no greater than about 1.6 cM. (C) 1996 Academic Press, Inc.

DOI PubMed CiNii

Detailed deletion mapping in squamous cell carcinomas of the esophagus narrows a region containing a putative tumor suppressor gene to about 200 kilobases on distal chromosome 9q(1)

K Miura, K Suzuki, T Tokino, M Isomura, J Inazawa, S Matsuno, Y Nakamura

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 56 ( 7 ) 1629 - 1634 1996.04

We previously reported definition of a region containing a putative tumor suppressor gene for esophageal squamous cell carcinoma within an similar to 4-cM genomic segment at 9q31-q32. We have investigated this region further using six new microsatellite markers isolated from yeast artificial chromosome clones covering the deleted region and have narrowly defined the commonly deleted region to a segment between two loci, KM9.1 and D9S177, On the basis of the contig map of cosmid and yeast artificial chromosome clones, we estimate the physical size of the region of interest to be about 200 kb, Because the distal 9q region also has been implicated as the site of a tumor suppressor gene(s) related to squamous cell carcinomas of other tissues, our map provides useful information for attempts to identify a common gene for carcinomas of this cell type.

MAPPING THE MOUSE GENE FOR PRIMARY CARNITINE DEFICIENCY

K OKITA, T TOKINO, H NISHIMORI, H NIKAIDO, J HAYAKAWA, A OHNO, M KUWAJIMA, Y MATSUZAWA, Y NAKAMURA

AMERICAN JOURNAL OF HUMAN GENETICS ( UNIV CHICAGO PRESS ) 57 ( 4 ) 1890 - 1890 1995.10

Research paper, summary (international conference)

TOPOLOGICAL CONTROL OF P21(WAF1/CIP1) EXPRESSION IN NORMAL AND NEOPLASTIC TISSUES

WS ELDEIRY, Takashi Tokino, T WALDMAN, JD OLINER, VE VELCULESCU, M BURRELL, DE HILL, E HEALY, JL REES, HAMILTON, SR, KW KINZLER, B VOGELSTEIN

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 55 ( 13 ) 2910 - 2919 1995.07

The p53-regulated gene product p21(WAF1/CIP1) is the prototype of a family of small proteins that negatively regulate the cell cycle. To learn more about p21(WAF1/CIP1) regulation in vivo, monoclonal antibodies were developed for immunohistochemistry. These revealed that p21(WAF1/CIP1) expression followed radiation-induced DNA damage in human skin in a pattern consistent with its regulation by p53. A detailed comparison of the human, rat, and mouse p21(WAF1/CIP1) promoter sequences revealed that this induction was probably mediated by conserved p53-binding sites upstream of the transcription start site. In unirradiated tissues, p21(WAF1/CIP1) expression was apparently independent of p53 and was observed in a variety of cell types. Moreover, there was a striking compartmentalization of p21(WAF1/CIP1) expression throughout the gastrointestinal tract that correlated with proliferation rather than differentiation. As epithelial cells migrated up the crypts, the Ki67-expressing proliferating compartment near the crypt base ended abruptly, with the coincident appearance of a nonproliferating compartment expressing p21(WAF1/CIP1). In colored neoplasms, this distinct compartmentalization was largely abrogated. Cell cycle inhibitors are thus subject to precise topological control, and escape from this regulation may be a critical feature of neoplastic transformation.

P53-DEPENDENT AND INDEPENDENT EXPRESSION OF P21 DURING CELL-GROWTH, DIFFERENTIATION, AND DNA-DAMAGE

KF MACLEOD, N SHERRY, G HANNON, D BEACH, T TOKINO, K KINZLER, B VOGELSTEIN, T JACKS

GENES & DEVELOPMENT ( COLD SPRING HARBOR LAB PRESS ) 9 ( 8 ) 935 - 944 1995.04

Expression of p21 has been shown to be up-regulated by the p53 tumor suppressor gene in vitro in response to DNA-damaging agents. However, p21 expression can be regulated independently of p53, and here we show that expression of p21 in various tissues during development and in the adult mouse occurs in the absence of p53 function. However, most tissues tested did require p53 for p21 induction following exposure of the whole animal to gamma irradiation. These results show that normal tissue expression of p21 to high levels is not dependent on p53 and confirm that induction of p21 by DNA-damaging agents does require p53. p21 is expressed upon differentiation of p53-deficient murine erythroleukemia (MEL) cells, and the kinetics of induction of p21 in this system suggest that it may be involved in the growth arrest that precedes terminal differentiation. The gene is up-regulated in mouse fibroblasts in response to serum restimulation but the kinetics and levels of induction differ between wild-type and mutant cells. Expression of p21 message following serum restimulation is superinducible by cycloheximide in wild-type but not in p53 deficient cells. The increases in p21 mRNA are reflected in changes in p21 protein levels. p21 expression also appears to be regulated at the post-transcriptional level because moderate increases in mRNA expression, during differentiation of MEL tells and upon serum restimulation of fibroblasts, are followed by large increases in protein levels, Regulation of the mouse p21 promoter by p53 depends on two critical p53-binding sites located 1.95 and 2.85 kb upstream from the transcriptional initiation site. The sequences mediating serum responsiveness of the promoter map to a region containing the proximal p53 site. p53 appears to play a critical role in p21 induction following DNA damage. Moreover, p21 can be regulated independently of p53 in several situations including during normal tissue development, following serum stimulation, and during cellular differentiation.

DOI PubMed CiNii

50 NOVEL SEQUENCE-TAGGED SITES (STSS) ON HUMAN-CHROMOSOME 11Q13.4-]Q25 IDENTIFIED FROM MICROCLONES GENERATED BY MICRODISSECTION

H SOEJIMA, K YOSHIURA, T TAMURA, T TOKINO, Y NAKAMURA, N NIIKAWA, Y JINNO

CYTOGENETICS AND CELL GENETICS ( KARGER ) 70 ( 1-2 ) 108 - 111 1995

Fifty sequence-tagged sites (STSs) from human chromosome region, 11q13.4-->q25 were identified in microdissection-generated microclones. From a total of 124 single-copy microclones obtained from regions 11q14-->q22 and 11q23-->q25, 59 were sequenced, and a PCR primer pair was designed for each of them. Fifty of the 59 dones were mapped to regions ranging from 11q13.4 to 11q25 by means of PCR on a somatic hybrid cell panel with various deletions of the long arm of human chromosome 11. These STSs will contribute to the construction of physical cosmid/YAC maps representing the chromosome regions. They are also useful for analysis of chromosome aberrations, such as translocations, inversions or marker chromosomes.

P53 TAGGED SITES FROM HUMAN GENOMIC DNA

T TOKINO, S THIAGALINGAM, WS ELDEIRY, T WALDMAN, KW KINZLER, B VOGELSTEIN

HUMAN MOLECULAR GENETICS ( OXFORD UNIV PRESS UNITED KINGDOM ) 3 ( 9 ) 1537 - 1542 1994.09

The product of the tumor suppressor gene p53 binds to DNA and activates transcription from promoters containing its consensus binding site. This activity has been hypothesized to be responsible for its biological effects. However, the total number and nature of human genomic sites with which p53 can functionally interact is unknown. In this paper, we have used a Saccharomyces cerevisiae-based screen to identify human genomic sequences that activate transcription from an adjacent reporter gene in a p53-dependent manner (p53-tagged sites, PTS). Fifty-seven different PTS were identified, and the total number of such sites in the human genome was predicted to be between 200 and 300. Almost all contained two adjacent copies of the previously defined consensus 5'-PuPuPuC(A/T)(T/A)GPyPyPy-3'. Spacing between the copies was found to be critical for sequence-specific transcriptional activation in vivo. These results further refine the nature of the genomic sequences likely to be most important for p53-mediated tumor suppression.

SEQUENCE-SPECIFIC TRANSCRIPTIONAL ACTIVATION IS ESSENTIAL FOR GROWTH SUPPRESSION BY P53

JA PIETENPOL, T TOKINO, S THIAGALINGAM, WS ELDEIRY, KW KINZLER, B VOGELSTEIN

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA ( NATL ACAD SCIENCES ) 91 ( 6 ) 1998 - 2002 1994.03

Although several biochemical features of p53 have been described, their relationship to tumor suppression remains uncertain. We have compared the ability of p53-derived proteins to act as sequence-specific transcriptional (SST) activators with their ability to suppress tumor cell growth, using an improved growth-suppression assay. Both naturally occurring and in vitro derived mutations that abrogated the SST activity of p53 lost the ability to suppress tumor cell growth. Additionally, the N- and C-terminal ends of p53 were shown to be functionally replaceable with foreign transactivation and dimerization domains, respectively, with concordant preservation of both SST and tumor-suppressive properties. Only the central region of p53, conferring specific DNA binding, was required to suppress growth by such hybrid proteins. The SST activity of p53 thus appeared to be essential for the protein to function as a tumor suppressor.

DOI PubMed CiNii

HIGH-RESOLUTION ORDERING OF DNA MARKERS BY MULTICOLOR FLUORESCENT IN-SITU HYBRIDIZATION OF PROPHASE CHROMOSOMES

J INAZAWA, T ARIYAMA, T TOKINO, A TANIGAMI, Y NAKAMURA, T ABE

CYTOGENETICS AND CELL GENETICS ( KARGER ) 65 ( 1-2 ) 130 - 135 1994

To improve resolution for physical ordering of adjacent DNA loci, prophase chromosomes were used for multi-color fluorescent in situ hybridization (FISH). The prophase chromosomes were prepared from cultured lymphocytes by a thymidine synchronization, bromodeoxyuridine release technique and then treating the synchronized cultures with topoisomerase II inhibitors ICRF154 or ICRF193. Almost all mitotic figures exhibited highly elongated prophase chromosomes without significant reduction of the mitotic index. Using multi-color FISH with these prophase chromosomes, we were able to distinguish signals for loci separated by as little as 50 kb, and determine their orientation. Furthermore, using this prophase ordering system, we confirmed the linear order and defined the orientation of seven cosmid markers within a 360-kb region surrounding D10S102, a locus that is closely linked to the disease locus in families segregating an allele causing multiple endocrine neoplasia IIA (MEN2A). This prophase FISH system, by rapidly and precisely providing the linear order of loci that are very close, can expedite construction of fine cytogenetic maps and contribute to positional-cloning studies in which the precise ordering of DNA loci in a target region is critical.

WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION

WS ELDEIRY, T TOKINO, VE VELCULESCU, DB LEVY, R PARSONS, JM TRENT, D LIN, WE MERCER, KW KINZLER, B VOGELSTEIN

CELL ( CELL PRESS ) 75 ( 4 ) 817 - 825 1993.11

The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. Introduction of WAF1 cDNA suppressed the growth of human brain, lung, and colon tumor cells in culture. Using a yeast enhancer trap, a p53-binding site was identified 2.4 kb upstream of WAF1 coding sequences. The WAF1 promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene. These studies define a gene whose expression is directly induced by p53 and that could be an important mediator of p53-dependent tumor growth suppression.

DOI PubMed CiNii

ABSENCE OF GERMLINE PROHIBITIN MUTATIONS IN EARLY-ONSET BREAST-CANCER

T TOKINO, N DAVIDSON, K HELZLSOUER, B ZEHNBAUER, Y NAKAMURA, B VOGELSTEIN, D SIDRANSKY

INTERNATIONAL JOURNAL OF ONCOLOGY ( INT JOURNAL ONCOLOGY ) 3 ( 4 ) 769 - 772 1993.10

The prohibitin gene, mapped to chromosome 17q21 is a candidate tumor suppressor gene. Because several somatic mutations of prohibitin were detected in breast tumors, we sought to identify potential carriers of prohibitin gene mutations in selected patients with early onset breast cancer. Seventy-six patients who developed breast cancer at or before the age of 40 were examined for mutations of prohibitin within the most conserved regions of the gene. Additionally, all exons of the prohibitin gene were examined in a subgroup of patients with a history of first-degree relatives with primary breast cancer. While several polymorphisms were noted, no inherited mutations of prohibitin were identified. This study suggests that prohibitin is not an early onset breast cancer susceptibility gene and additional studies will be necessary to understand its role in sporadic breast cancer progression.

IDENTIFICATION AND CHARACTERIZATION OF A 9-KB SOMATIC HOMOZYGOUS DELETION AT 3P21.3-P22 IN A LUNG-CANCER CELL-LINE

K YAMAKAWA, Y MURATA, M TAMARI, T TAKAHASHI, Y HORIO, K HIBI, S YOKOYAMA, J INAZAWA, T TAKAHASI, Y NAKAMURA

AMERICAN JOURNAL OF HUMAN GENETICS ( UNIV CHICAGO PRESS ) 53 ( 3 ) 390 - 390 1993.09

Research paper, summary (international conference)

P53 MUTATION AND MDM2 AMPLIFICATION IN HUMAN SOFT-TISSUE SARCOMAS

FS LEACH, T TOKINO, P MELTZER, M BURRELL, JD OLINER, S SMITH, DE HILL, D SIDRANSKY, KW KINZLER, B VOGELSTEIN

CANCER RESEARCH ( AMER ASSOC CANCER RESEARCH ) 53 ( 10 ) 2231 - 2234 1993.05

Article, review, commentary, editorial, etc. (scientific journal)

The p53 and MDM2 genes were analyzed in 24 human soft tissue sarcomas (11 malignant fibrous histiocytomas and 13 liposarcomas). Alterations of p53, consisting of point mutations, deletions, or overexpression, were detected in one-third (8 of 24) of the sarcomas. MDM2 gene amplification was detected in another 8 tumors, but no tumor contained an alteration of both genes. Monoclonal antibodies reactive with the human MDM2 gene product were developed, and immunohistochemical analysis revealed nuclear localization and overexpression of MDM2 in those tumors with amplified MDM2 genes. These data support the hypothesis that p53 and MDM2 genetic alterations are alternative mechanisms for inactivating the same regulatory pathway for suppressing cell growth.

MAPPING THE BREAKPOINT OF A CONSTITUTIONAL TRANSLOCATION ON CHROMOSOME-22 IN A PATIENT WITH NF2

E ARAI, T TOKINO, T IMAI, J INAZAWA, T IKEUCHI, A TONOMURA, Y NAKAMURA

GENES CHROMOSOMES & CANCER ( WILEY-LISS ) 6 ( 4 ) 235 - 238 1993.04

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by development of bilateral acoustic neurinomas and increased incidence of meningiomas. Frequent losses of 1 allele of chromosome 22 in neurinomas and meningiomas has indicated that the gene responsible for NF2 functions as a tumor suppressor. Although the NF2 gene has been mapped within a 13 cM region between D22S1 and D22S28 by linkage analysis, its location with respect to D22S15 is uncertain. We previously reported an NF2 patient with a constitutional balanced translocation t(4;22) (q12;q12.2); the NF2 gene is probably disrupted at the breakpoint. To define the location of this breakpoint on chromosome 22, we performed fluorescence in situ hybridization (FISH) with DNA markers in the NF2 region and determined the physical order of 5 loci: D22S1-NF2-LIF-D22S15-D22S32.

DOI PubMed CiNii

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