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論文 - 佐谷　秀行

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Tight-binding inhibitory sequences against pp60(c-src) identified using a random 15-amino-acid peptide library

Nishi Toru, Budde Raymond J A, McMurray John S., Obeyesekere Nihal U., Safdar Naueen, Levin Victor A., Saya Hideyuki

FEBS Letters 399 （ 3 ） 237 - 240 1996年12月

ISSN 0014-5793

A bacteriophage peptide library containing a random 15-amino-acid insert was screened for identification of peptide sequence(s) that bind pp60(c-src). Sequencing the random insert from more than 100 virions indicated that more than 60% of the phage virions that bound to this enzyme contained a GXXG sequence motif in which X was frequently a hydrophobic residue. The GXXG sequence was often repeated as GXXGXXG. Two nonameric peptides were synthesized to determine whether or not the peptide inhibits pp60(c-src) tyrosine kinase activity and the importance of the glycine residues within this sequence. The peptide containing glycine had a K(i) of 24 μM, whereas replacing the glycines with proline increased the K(i) value to 3.1 mM.

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Receptor protein tyrosine kinase DDR is up-regulated by p53 protein

Sakuma Shirou, Saya Hideyuki, Tada Mitsuhiro, Nakao Mitsuyoshi, Fujiwara Toshiyoshi, Roth Jack A., Sawamura Yutaka, Shinohe Yumiko, Hiroshi Abe

FEBS Letters 398 （ 2-3 ） 165 - 169 1996年12月

ISSN 0014-5793

We have previously reported on radiation-induction of ptk-3 in rat astr ocyte culture [Sakuma et al. (1995) Radiat. Res. 143, 1-7]. Ptk-3 was considered to be a rat version of human DDR (discoidin domain receptor). We cloned and analyzed genomic DNA of the DDR and its promoter region. We discovered that the promoter region contained a consensus sequence of the p53 tumor suppressor binding site. Adenovirus-mediated p53 transfection induced a high level of DDR mRNA in SAOS2 human osteosarcoma cells. These results indicate that DDR is up-regulated by the p53 protein.

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Evidence for p53-mediated modulation of neuronal viability

Xiang Hong, Hochman Daryl W., Saya Hideyuki, Fujiwara Toshiyoshi, Schwartzkroin Philip A., Morrison Richard S.

Journal of Neuroscience 16 （ 21 ） 6753 - 6765 1996年11月

ISSN 0270-6474

A role for p53-related modulation of neuronal viability has been suggested by the finding that p53 expression is increased in damaged neurons in models of ischemia and epilepsy. These findings were recently extended with the demonstration that mice deficient in p53 ('knock-out' mice) exhibit almost complete protection from seizure-induced brain injury, whereas wild- type mice display significant neuronal cell loss in the hippocampus and other brain regions. Because the p53 knockout mice used in the latter study expressed a global p53 deficiency in all cell types, it was not possible to conclude that protection was conferred by the exclusive absence of p53 in neurons. Therefore, in the present study, we determined whether p53 expression in isolated neurons is directly coupled to a loss of viability associated with excitotoxic challenge. Primary cultures of hippocampal or cortical neurons were derived from animals containing p53 (+/+, +/-) or those deficient in p53 (-/-). p53-Deficient neurons appeared identical to wild- type neurons with respect to morphology, neurofilament expression, and resting levels of intracellular calcium. Neurons containing at least one copy of p53 were severely damaged by exposure to kainic acid or glutamate. Cell damage was assessed by direct cell counting and by nuclear morphology after propidium iodide staining of DNA. In contrast, neurons deficient in p53 (-/- ) exhibited little or no damage in response to excitotoxin treatment. Despite their divergent outcomes, p53 (+/+) and p53 (-/-) neurons demonstrated similar sustained elevations in intracellular calcium levels triggered by glutamate exposure. Restoring p53 expression to p53-deficient neurons, using adenovirus-mediated transduction, was sufficient to promote neuronal cell death even in the absence of excitotoxin. These results demonstrate a direct relationship between p53 expression and loss of viability in CNS neurons.

Phosphorylation of neurofibromatosis type 1 gene product (neurofibromin) by cAMP-dependent protein kinase

Izawa Ichiro, Tamaki Norihiko, Saya Hideyuki

FEBS Letters 382 （ 1-2 ） 53 - 59 1996年03月

ISSN 0014-5793

The critical function of the neurofibromatosis type 1 (NF1) gene product (neurofibromin) is not well defined except that neurofibromin has homology with a family of the GTPase-activating proteins (GAPs). In this study, we confirmed that neurofibromin is constitutively phosphorylated and detected kinase activities which specifically phosphorylate the cystein/serine-rich domain and the C-terminal domain of the neurofibromin in cell lysate. In vitro and in-gel kinase assays strongly indicated that cAMP-dependent protein kinase (PKA) is a candidate for the neurofibromin kinase. The biological significance of the phosphorylation of neurofibromin is unclear at present, but we speculate that neurofibromin plays a crucial role in cellular function since it links the two major cellular pathways which are the GAP-ras and PKA-associated signals.

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High-efficiency in vivo gene transfer using intraarterial plasmid DNA injection following in vivo electroporation

Nishi Toru, Yoshizato Kimio, Yamashiro Shigeo, Takeshima Hideo, Sato Kyoichi, Hamada Kazuya, Kitamura Isao, Yoshimura Teizo, Saya Hideyuki, Kuratsu Jun Ichi, Ushio Yukitaka

Cancer Research 56 （ 5 ） 1050 - 1055 1996年03月

ISSN 0008-5472

A novel method for high-efficiency and region-controlled in vivo gene transfer was developed by combining in vivo electroporation and intraarterial plasmid DNA injection. A mammalian expression plasmid for the Escherichia coli lacZ gene (driven with a SV40 early promoter) was injected into the internal carotid artery of rats whose brain tumors (from prior inoculation) had been electroporated between two electrodes. The lacZ gene was efficiently transferred and expressed in the tumor cells 3 days after plasmid injection. However, neither any gene transfers nor any elevated lacZ activity was detected in tissues outside the electrodes. The plasmid was not transferred without electroporation. Human monocyte chemoattractant protein-1 cDNA was also transferred by this method, and its long-lasting (3 weeks) expression was confirmed by using the Epstein-Barr virus episomal replicon system. The expressed monocyte chemoattractant protein-1 protein was functional, as evident by the presence of a large number of monocytes in the tumor tissue. This method, 'electrogene therapy,' which does not require viral genes or particles, allows genes to be transferred and expressed in desired organs or tissues, and it may lead to the development of a new type of highly effective gene therapy.

Transfection of wild-type TP53 induces differentiation in human gingival carcinoma cells

Takahashi R., Inagaki T., Matsuwari S., Fujioka M., Maeda S., Ijuhin N., Haga H., Koh T., Shimada K., Saya H.

European Journal of Cancer 32 （ 3 ） 533 - 539 1996年03月

ISSN 0959-8049

We investigated the effects of transfection of wild-type TP53 on the growth properties of a human gingival carcinoma cell line, KOSC-3, in which the TP53 gene is mutated at codon 248 and overexpressed. The wild-type TP53 expression plasmid, pCDM8-p53/neo and the control plasmid, pCDM8/neo, were each stably transfected into KOSC-3 cells by using the calcium phosphate method. The number of G418-resistant colonies from wild-type TP53-transfected cells was approximately half that from plasmid controls. Exogenous wild-type TP53 transcripts were identified in four of the 20 G418-resistant clones analysed by reverse transcription PCR. Although the growth rates of the wild-type TP53+ clones did not drastically change during log phase, their saturation density was significantly reduced. The wild-type TP53+ cells were morphologically flat and enlarged when cultured in vitro, and were less able to form colonies in soft agar. In nude mice, the wild-type TP53+ clones formed subcutaneous tumours with conspicuous keratinisation and notable cell death that was not manifested in the parental and plasmid control cells. These findings indicate that the wild-type TP53 gene, even when it coexists with a mutated form, may function as a growth suppressor and differentiation inducer under restricted conditions in gingival squamous cell carcinoma.

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Oncogenes and tumor suppressor genes

Saya Hideyuki

Japanese Journal of Human Genetics 41 （ 1 ） 18 1996年

ISSN 0916-8478

Proliferation and differentiation of cells are known to be regulated by complicated interactions in which various intracellular molecules are involved. Recent molecular genetic analyses have revealed that the genesis and progression of tumors are the result of accumulated changes in two major classes of growthregulatory genes - the oncogenes and the tumor suppressor genes. Several sequential genetic alterations, especially the inactivation of tumor suppressor genes, appear to allow cells to develop toward a more malignant phenotype. More than 10 tumor suppressor genes have been identified since the retinoblastoma susceptibility gene (RB1) was found as the first suppressor gene of mammalian cells in 1986. These genes can be grouped into four classes according to the functions; genes which are involved in 1) regulation of cell cycle, 2) DNA mismatch repair pathway, 3) cell-cell contact signals, and 4) regulation of ras proto-oncogene product. Especially, genes which encode cell cycle regulatory proteins such as RB1, p53, and p!6 have been found to have frequent mutations in various cancer cells, and these functions are rapidly being characterized. The biochemical characters of these cell cycle regulators will be discussed.

Imprinted regulation in the region of Prader-Willi and Angelman syndromes

Nakao Mitsuyoshi, Anan Tadashi, Saya Hideyuki, Sutcliffe James S., Gunaratne Preethi H., Beaudet Arthur L.

Japanese Journal of Human Genetics 41 （ 1 ） 84 1996年

ISSN 0916-8478

Prader-Willi syndrome(PWS) and Angelman syndrome(AS) are distinct clinical phenotypes resulting from paternal and maternal deficiencies respectively in human chromosome 15qll-ql3, and are caused by deletion, uniparental disomy, or other mutations. Three paternally expressed transcripts containing small nuclear ribonucleoproteinassociated polypeptide N(SNRPN), PAR-5 and PAR-1 were absent in cultured cells from PWS patients with a small deletion that involve a differentially methylated CpG island around a 5' untranslated exon alpha of SNRPN gene. Methylation of the CpG island is specific for the maternal chromosome consistent with paternal expression of the imprinted domain. The small deletion, which is benign when maternally transmitted, extends upstream 50 kb from the CpG island, and results in the loss of expression of the three imprinted transcripts, altered methylation and replication timing around SNRPN gene, implying the presence of an imprinting control element.

Microsatellite analysis of chromosome 10q in malignant glioma

Nakamura Hideo, Nakao Mitsuvoshi, Saya Hideyuki, Kuratsu Jun Ichi, Ushio Yukitaka

Japanese Journal of Human Genetics 41 （ 1 ） 57 1996年

ISSN 0916-8478

Chromosome 10 is frequently deleted in malignant gliomas and the frequency of the deletion is known to be related to clinical and pathological malignancy of the tumor. Therefore, we expect that certain genes which is implicated in malignancy of glioma are located on chromosome 10. Here, we analyze the loss of heterozygosity (LOH) of microsatellite markers on chromosome lOq by PCR using fluorescentry-labelled primer. D10S201, D10S200, D10S603, D10S192, D10S205, D10S222, D10S540, D10S566, D10S530, D10S597, D10S545, D10S587, D10S186, and D10S212 were used for this analysis. LOH of the markers were quantitatively analyzed by an automated DNA fragment analyzer and a software. Using this system, we found LOH in 19 of 43 cases of malignant gliomas, and the most frequent deletion was identified at D10S 566 region.

CD44 hyaluronate binding influences growth kinetics and tumorigenicity of human colon carcinomas

Takahashi K., Stamenkovic I., Cutler M., Saya H., Tanabe K. K.

Oncogene 11 （ 11 ） 2222 - 2232 1995年12月

ISSN 0950-9232

CD44 is a cell surface receptor for hyaluronate that is implicated in the regulation of tumor growth and metastatic potential. Transformation of colon mucosa to carcinoma is associated with overexpression of several CD44 alternative splice variants. The functional roles of CD44 isoforms in colon carcinoma tumor progression remain unclear. CD44H expression is downregulated in colon carcinomas compared to paired normal mucosa. In the present study we demonstrate that reintroduction of CD44H back into colon carcinoma cells by stable transfection reduces their in vitro growth rate and tumorigenicity. Examination of several colon carcinoma cell lines and use of mutant CD44H reveal that this in vitro and in vivo growth reduction requires the ability of CD44H to bind hyaluronate. These observations indicate that the CD44H downregulation associated with transformation of mucosa to colon carcinoma may provide the carcinoma cells with a growth advantage. Furthermore, the reduction in tumor growth rate mediated by reintroduction of CD44H into colon carcinoma cells is dependent on its ability to bind hyaluronate.

Induction of Fas-mediated apoptosis in p53-transfected human colon carcinoma cells

Tamura T., Aoyama N., Saya H., Haga H., Futami S., Miyamoto M., Koh T., Ariyasu T., Tachi M., Kasuga M., Takahashi R.

Oncogene 11 （ 10 ） 1938 - 1946 1995年11月

ISSN 0950-9232

To investigate the biological function of p53 in colon carcinoma cells, a wild-type p53 expression plasmid under the control of the human cytomegalovirus promoter was stably transfected into the human colon adenocarcinoma cell line WiDr, which carries a mutation of the p53 gene at codon 273. Exogenous wild-type p53 transcripts were detected at various expression levels in 8 of 117 G418-resistant clones. The growth rates of the wild-type p53+ clones in culture did not change significantly. The efficiency of colony formation in soft agar, however, was completely suppressed in two wild-type p53+ clones. This is the first to demonstrate the feasibility of stable transfection of the wild-type p53 gene under the control of non-inducible promoter in human colon cancer cells. The major alteration found was that wild-type p53+ cells which were incubated with anti-Fas IgM showed marked cytolysis with preferential overexpression of wild-type p53 accompanied by overexpression of a cyclin-dependent kinase inhibitor, WAF1, whereas the endogenous mutant p53 retained its expression level. The findings suggest that a Fas-initiated pathway is incidentally linked to a p53-dependent apoptotic pathway through the reconstituted wild-type p53 gene in WiDr cells. This model should help elucidating the additional role of the p53 tumor suppressor gene and the mechanism of apoptosis in colon carcinoma cells.

Implication of cell cycle regulating genes in carcinogenesis

Hanada N., Saya H.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 40 （ 11 ） 1713 - 1720 1995年08月

ISSN 0039-9450

Discovery, development, and testing of substrates and inhibitors of pp60^c-SRC

Budde Raymond J A, Mcmurray John S., Saya Hideyuki, Gallick Gary E., Levin Victor A.

Pharmaceutical Biology 33 （ S1 ） 27 - 34 1995年

ISSN 1388-0209

Currently, there are no specific protein tyrosine kinase inhibitors available. This review summarizes our efforts to develop an active-site-directed inhibitor of pp60^c-srv Initial efforts are directed at determining substrate specificity with synthetic peptides and at developing a biological system to test the potential of pp60^c-src inhibitors to effectively inhibit the growth of pp60^c-src activated cell lines. To meet these goals, we have developed new methods for purifying recombinant pp60^C-SRC, assaying tyrosine kinase activity, synthesizing cyclic peptides, and generating random peptide libraries. In addition, we discuss the generation of potential artifacts while using polyhydroxy aromatic compounds as tyrosine kinase inhibitors.

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Discovery, development, and testing of substrates and inhibitors of pp60(c-src)

Budde R. J A, McMurray J. S., Saya H., Gallick G. E., Levin V. A.

International Journal of Pharmacognosy 33 （ SUPPL. ） 27 - 34 1995年

ISSN 0925-1618

Currently, there are no specific protein tyrosine kinase inhibitors available. This review summarizes our efforts to develop an active-site-directed inhibitor of pp60(c-src). Initial efforts are directed at determining substrate specificity with synthetic peptides and at developing a biological system to test the potential of pp60(c-src) inhibitors to effectively inhibit the growth of pp60(c-src) activated cell lines. To meet these goals, we have developed new methods for purifying recombinant pp60(c-src), assaying tyrosine kinase activity, synthesizing cyclic peptides, and generating random peptide libraries. In addition, we discuss the generation of potential artifacts while using polyhydroxy aromatic compounds as tyrosine kinase inhibitors.

Alternative RNA splicing of the hyaluronic acid receptor CD44 in the normal human brain and in brain tumors

Nagasaka S., Tanabe K. K., Bruner J. M., Saya H., Sawaya R. E., Morrison R. S.

Journal of Neurosurgery 82 （ 5 ） 858 - 863 1995年

ISSN 0022-3085

The cell-surface receptor for hyaluronic acid, CD44, is expressed by both normal and malignant cells. Numerous CD44 isoforms have recently been identified that are derived by alternative ribonucleic acid splicing. The expression of some CD44 isoforms has been shown to be involved in tumor progression and metastatic spread in a rat carcinoma model and in human carcinomas. In the present study, CD44 isoform expression was evaluated by reverse transcriptase-polymerase chain reaction (PCR) analysis in frozen sections derived from three samples of normal brain tissue and from 40 brain tumors, including samples of glioblastoma multiforme, anaplastic astrocytoma, low-grade astrocytoma, cerebral primitive neuroectodermal tumor, medulloblastoma, metastatic colon carcinoma, and metastatic melanoma. Normal brain tissue adjacent to the tumors was also examined in 14 of 18 glioblastomas. In all normal brain and tumor samples, with the exception of metastases from colon carcinoma, PCR analysis demonstrated one prominent product that corresponded to the CD44H hematopoietic form of CD44. Metastases from colon carcinoma demonstrated two prominent PCR amplification products corresponding to CD44H and CD44R1. These results suggest that CD44H is the predominant isoform of this protein in normal human brain tissue and in human neuroectodermal tumors of varying degrees of malignancy. The ability of CD44H to mediate tumor cell motility and invasiveness (in contrast to CD44R1) suggests that the CD44 alternative splicing pattern of neuroectoderm-derived tumors may enhance their local biological aggressiveness and intracerebral spread. The lack of expression of larger molecular weight CD44 variants by primary brain tumors may also partially explain why these tumors rarely metastasize to distant sites.

Radiation induction of the receptor tyrosine kinase gene Ptk-3 in normal rat astrocytes

Sakuma S., Saya H., Ijichi A., Tofilon P. J.

Radiation Research 143 （ 1 ） 1 - 7 1995年

ISSN 0033-7587

Radiation-induced gene expression was examined in rat astrocyte cultures using differential display of mRNA via reverse transcriptase-polymerase chain reaction. A 0.3-kb cDNA that was consistently observed in irradiated cultures but not in unirradiated cultures was cloned and sequenced. It was found to be identical to Ptk-3, a receptor tyrosine kinase gene identified recently. The protein encoded by Ptk-3 is a member of a novel class of receptor tyrosine kinases whose extracellular domain contains regions of homology with coagulation factors V and VIII and complement component C1. Northern blot analysis revealed that the expression of Ptk-3 was increased in rat astrocytes by 0.5 h after exposure to 10 Gy and remained at the same elevated level for at least 24 h. The maximum increase occurred after 5 Gy. Cloning studies indicated the presence of at least two Ptk-3 mRNA transcripts, which are probably the result of an alternative splicing mechanism. The short isoform lacks a 37-amino acid sequence in the glycine/proline-rich juxtamembrane region. The splicing pattern of the Ptk-3 gene was not altered by radiation. However, the ratios of the longer to the shorter mRNA transcripts differed between adult cortex, neonatal cortex and in vitro astrocyte cultures.

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Basic fibroblast growth factor and fibroblast growth factor receptor I are implicated in the growth of human astrocytomas

Morrison Richard S., Yamaguchi Fumio, Saya Hideyuki, Bruner Janet M., Yahanda Alan M., Donehower Lawrence A., Berger Mitchel

Journal of Neuro-Oncology 18 （ 3 ） 207 - 216 1994年10月

ISSN 0167-594X

Malignant astrocytomas are highly invasive, vascular neoplasms that comprise the majority of nervous system tumors in humans. A strong association has previously been made between malignancy in human astrocytic tumors and increased expression of certain fibroblast growth factor (FGF) family members, including basic and acidic FGF. The influence of endogenous basic FGF on glioblastoma cell growth in vitro was evaluated using basic FGF-specific antisense oligonucleotides. These studies indicated that human glioblastoma cell growth in vitro, can be inhibited by suppressing basic FGF expression. Human astrocytomas also exhibited changes in FGF receptor (FGFR) expression during the course of their progression from a benign to a malignant phenotype. FGFR2 (bek) expression was abundant in normal white matter and in all low grade astrocytomas, but was not observed in glioblastomas. Conversely, FGFR1 (flg) expression was absent or barely detectable in normal white matter, but was significantly elevated in glioblastomas. Glioblastomas also expressed an alternatively spliced form of FGFR1 containing two immunoglobulin-like disulfide loops (FGFR1β), whereas normal human adult and fetal brain expressed a form of the receptor containing three immunoglobulin-like disulfide loops (FGFR1α). Intermediate grades of astrocytic tumors exhibited a gradual loss of FGFR2 and a shift in expression from FGFR1α to FGFR1β as they progressed from a benigh to a malignant phenotype. The underlying cytogenetic changes that contribute to these alterations are not entirely understood, but abnormalities in the p53 tumor suppressor gene may influence expression of bFGF as well as the FGFR. These results suggest that alterations in FGFR signal transduction pathways may play a critical role in the malignant progression of astrocytic tumors.

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Detection of cellular proteins that interact with the NF2 tumor suppressor gene product

Takeshima Hideo, Izawa Ichiro, Lee Polly S Y, Safdar Naueen, Levin Victor A., Saya Hideyuki

Oncogene 9 （ 8 ） 2135 - 2144 1994年08月

ISSN 0950-9232

The neurofibromatosis type 2 (NF2) gene was recently cloned, and the protein it encodes (merlin) was revealed to belong to a family of proteins that link cytoskeletal components with proteins in the cell membrane. To elucidate the biological function of merlin, we produced a bacterial fusion protein consisting of glutathione S-transferase and merlin and used it to detect five merlin-binding cellular proteins, designated p165, p145, p125, p85 and p70, by a protein-binding assay. p165 and merlin were phosphorylated on serine/threonine residues, and immunoprecipitation showed that p85 bound the native form of merlin. Although the entire merlin-ezrin-radixin-moesin (MERM) homology domain of merlin was found to be essential for binding to all five proteins, the MERM homology domains of ezrin and moesin did not bind to any of the five proteins. Since most reported NF2 mutations are in the region we determined was necessary for binding, the mutations probably impair binding. Therefore, the formation of the protein complex is probably crucial for tumor suppression.

Germline p53 gene mutations in subsets of glioma patients

Kyritsis Athanassios P., Bondy Melissa L., Xiao Mi, Berman Elise L., Cunningham Joan E., Lee Polly S., Levin Victor A., Saya Hideyuki

Journal of the National Cancer Institute 86 （ 5 ） 344 - 349 1994年03月

ISSN 0027-8874

Background: Heritable germline mutations of the p53 gene have been described in patients with Li-Fraumeni syndrome, occasionally in nonfamilial malignancies such as multifocal osteosarcoma, in a small subgroup of young patients with two or more primary malignancies, and in patients with sporadic breast carcinoma. We recently reported that multifocal gliomas are frequently associated with other primary malignancies, and we hypothesized that genetic alterations may account for this phenomenon. Purpose: We examined the frequency of germline p53 gene mutations in patients with glioma and either multifocality of lesions, history of an additional primary (different) malignancy, or a family history of cancer. Methods: Lymphocytes from 51 glioma patients were analyzed for germline p53 gene mutations using RNA- polymerase chain reaction analysis, single-strand conformation polymorphism, and gene sequencing techniques. Results: Germline p53 gene mutations were detected in six of 19 patients with multifocal glioma, including two with family history of cancer, one with another primary malignancy, and two with all three risk factors; one of four patients with unifocal glioma, another primary malignancy, and a family history of cancer; and two of 15 patients with unifocal glioma and a family history of cancer but no second malignancies. No mutations were detected in the patient with unifocal glioma and another malignancy or in the 12 control patients with unifocal glioma and no second malignancies or family history of cancer. Patients having mutations were younger than other patients in the same group. Conclusions: Germline p53 mutations are frequent in patients with multifocal glioma, glioma and another primary malignancy, and glioma associated with a family history of cancer, particularly if these factors are combined. Implications: Relatives at high risk can be identified for genetic counseling, early cancer detection, and possible enrollment in chemoprevention trials.

Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas

Yamaguchi Fumio, Saya Hideyuki, Bruner Janet M., Morrison Richard S.

Proceedings of the National Academy of Sciences of the United States of America 91 （ 2 ） 484 - 488 1994年01月

ISSN 0027-8424

Malignant astrocytomas, which are highly invasive, vascular neoplasms, compose the majority of nervous system tumors in humans. Elevated expression of fibroblast growth factors (FGFs) in astrocytomas has implicated the FGF family of mitogens in the initiation and progression of astrocyte-derived tumors. In this study, we demonstrated that human astrocytomas undergo parallel changes in FGF-receptor (FGFR) expression during their progression from a benign to a malignant phenotype. FGFR type 2 (BEK) expression was abundant in normal white matter and in all low-grade astrocytomas but was not seen in malignant astrocytomas. Conversely, FGFR type 1 (FLG) expression was absent or barely detectable in normal white matter but was significantly elevated in malignant astrocytomas. Malignant astrocytomas also expressed an alternatively spliced form of FGFR-1 (FGFR-1β) containing two immunoglobulin-like disulfide loops, whereas normal human adult and fetal brains expressed a receptor form (FGFR-1α) containing three immunoglobulin- like disulfide loops. Intermediate grades of astrocytic tumors exhibited a gradual loss of FGFR-2 and a shift in expression from FGFR-1α to FGFR-1β as they progressed from benign to malignant phenotype. These results suggest that differential expression and alternative splicing of FGFRs may be critical in the malignant progression of astrocytic tumors.

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