研究者詳細 - 西原　広史

論文 - 西原　広史

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Crk associates with ERM proteins and promotes cell motility toward hyaluronic acid.

Tsuda M, Makino Y, Iwahara T, Nishihara H, Sawa H, Nagashima K, Hanafusa H, Tanaka S

The Journal of biological chemistry （45） 279 （ 45 ） 46843 - 46850 2004年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9258

Cell migration is a well organized process regulated by the extracellular matrix-mediated cytoskeletal reorganization. The signaling adaptor protein Crk has been shown to regulate cell motility, but its precise role is still under investigation. Herein, we report that Crk associates with ERM family proteins ( including ezrin, radixin, and moesin), activates RhoA, and promotes cell motility toward hyaluronic acid. The binding of Crk with ERMs was demonstrated both by transient and stable protein expression systems in 293T cells and 3Y1 cells, and it was shown that v-Crk translocated the phosphorylated form of ERMs to microvilli in 3Y1 cells by immunofluorescence and immunoelectron microscopy. This v-Crk-dependent formation of microvilli was suppressed by inhibitors of Rho-associated kinase, and the activity of RhoA was elevated by coexpression of c-Crk-II and ERMs in 3Y1 cells. In concert with the activation of RhoA by Crk, Crk was found to associate with Rho-GDI, which has been shown to bind to ERMs. Furthermore, upon hyaluronic acid treatment, coexpression of c-Crk-II and ERMs enhanced cell motility, whereas the sole expression of c-Crk-II or either of the ERMs decreased the motility of 3Y1 cells. These results suggest that Crk may be involved in regulation of cell motility by a hyaluronic acid-dependent mechanism through an association with ERMs.

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Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK.

Nishihara H, Hwang M, Kizaka-Kondoh S, Eckmann L, Insel PA

The Journal of biological chemistry （25） 279 （ 25 ） 26176 - 26183 2004年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9258

We recently reported that cAMP suppresses apoptosis in colon cancer cells and induces cellular inhibitor of apoptosis protein-2 (c-IAP2) via a cAMP-responsive element (CRE), suggesting a mechanism for chemoprevention of colon cancer by non-steroidal anti-inflammatory drugs. In this study, we used T84 human colon cancer cells to define the pathway by which increases in cAMP induce c-IAP2 expression. Treatment with several different cAMP agonists stimulated phosphorylation of CRE-binding protein (CREB) and activated expression of c-IAP2 in a CREB-dependent manner. Studies with pharmacological inhibitors revealed that cAMP-dependent phosphorylation of CREB required activation of ERK1/2 and p38 MAPK but was largely independent of protein kinase A. Immunoblots and transcriptional reporter assays using specific inhibitors, as well as expression of constitutively active forms of MEK1 and MKK3, showed that c-IAP2 induction by cAMP is regulated predominantly through ERK1/2 and p38 MAPK and suggested involvement of p90 ribosomal protein S6 kinase and mitogen and stress response kinase-1 as well. Consistent with those results, we found that cAMP-dependent suppression of apoptosis was blocked by treatment with inhibitors of ERK1/2 and p38 MAPK. We conclude that cAMP can induce c-IAP2 expression in colon cancer cells through CREB phosphorylation and CRE-dependent transcription in a manner that involves activation of ERK1/2 and p38 MAPK. These results emphasize that activation of kinases other than protein kinase A can mediate the actions of agents that increase cAMP, particularly in the regulation of CREB-dependent events.

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Application of laser capture microdissection to cytologic specimens for the detection of immunoglobulin heavy chain gene rearrangement in patients with malignant lymphoma.

Orba Y, Tanaka S, Nishihara H, Kawamura N, Itoh T, Shimizu M, Sawa H, Nagashima K

Cancer （4） 99 （ 4 ） 198 - 204 2003年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0008-543X

BACKGROUND. The demonstration of the monoclonality of immunoglobulin heavy chain (IgH) gene rearrangement is an indispensable method for the diagnosis of B-cell lymphoma as well as histocytochemical analysis. For the detection of IgH gene rearrangement, the extraction of DNA from a homogenous cell population is necessary. Recently, the laser capture microdissection (LCM) technique was shown to isolate specific cells from histopathologic specimens for molecular analysis. However, to the authors' knowledge the applicability of LCM to cytologic specimens has not yet been well established.
METHODS. Using LCM, a homogenous population of B-cell lymphoma cells as both histologic sections and cytologic specimens was captured, and genomic DNA was extracted from the captured cells. IgH gene rearrangement was analyzed by the polymerase chain reaction (PCR)-based single-strand conformational polymorphism (SSCP) method.
RESULTS. Genomic DNAs were extracted successfully from ethanol-fixed cytologic specimens, but cells were not captured from air-dried specimens. Using PCR-SSCP analysis, the monoclonality of the IgH gene rearrangement was detected in five cases of tissue sections among nine analyzed cases of malignant lymphoma diagnosed immunohistochemically. However, analysis of the cytologic specimens with LCM demonstrated the monoclonality of the IgH gene rearrangement in seven cases of lymphoma.
CONCLUSIONS. The results of the current study suggest that the novel application of LCM to cytologic specimens occasionally exhibits high sensitivity for the detection of IgH gene rearrangement monoclonality compared with the use of histologic sections.

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Inhibition of apoptosis in normal and transformed intestinal epithelial cells by cAMP through induction of inhibitor of apoptosis protein (IAP)-2.

Nishihara H, Kizaka-Kondoh S, Insel PA, Eckmann L

Proceedings of the National Academy of Sciences of the United States of America （15） 100 （ 15 ） 8921 - 8926 2003年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0027-8424

Cyclooxygenase (COX)-2, a rate-limiting enzyme of prostaglandin (PG) production, is overexpressed in colorectal adenomas and adenocarcinomas, and its inhibition by nonsteroidal antiinflammatory drugs protects against colorectal cancer. Mechanisms of cancer promotion by COX-2 are not fully understood, but signaling through prostaglandin (PG)E-2 receptors is a contributing factor. The major PGE(2) receptors on epithelial cells, EP2 and EP4, increase cAMP production, which promotes growth and inhibits apoptosis in some cell types. Here, we show that cAMP agonists, including PGE2, cholera toxin, and a membrane-permeant cAMP analog, protect normal and transformed intestinal epithelial cells from apoptosis induced by diverse stimuli. This protection is associated with cAMP-mediated, rapid induction of cellular inhibitor of apoptosis protein (c-IAP)-2 and delayed induction of LIVIN, but not of six other members of the IAP family. Concurrently and characteristic of IAP functions, the activity, but not generation, of the cleaved form of the central executioner caspase 3 is inhibited. Induction of c-IAP2 expression by cAMP agonists is accompanied by phosphorylation of cAMP response element binding protein and cAMP response element-dependent activation of transcriptional reporters. Furthermore, inhibition of COX-2 in cells overexpressing the enzyme decreases c-IAP2 expression and promotes apoptosis, both of which are reversible by PGE2 addition, suggesting that COX-2-promoted antiapoptosis is mediated by release of PGE2 and subsequent cAMP-dependent c-IAP2 induction. These results help to explain the cancer chemoprotective effects of nonsteroidal anti inflammatory drugs by defining a mechanism through which cAMP signaling can promote the development of colorectal and possibly other epithelial cancers by means of disruption of normal apoptotic processes.

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CrkL directs ASAP1 to peripheral focal adhesions.

Oda A, Wada I, Miura K, Okawa K, Kadoya T, Kato T, Nishihara H, Maeda M, Tanaka S, Nagashima K, Nishitani C, Matsuno K, Ishino M, Machesky LM, Fujita H, Randazzo P

The Journal of biological chemistry （8） 278 （ 8 ） 6456 - 6460 2003年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9258

Searching for proteins in platelets that can interact with the N-terminal SH3 domain of CrkL (using a combination of a pull-down assay followed by mass spectrometry), we have found that human platelets express an ADP-ribosylation factor (Arf)-specific GTPase-activating protein (GAP), ASAP1, as a CrkL-binding protein. In spreading platelets, most endogenous ASAP1. is localized at peripheral focal adhesions. To determine the physiologic significance of the CrkL-ASAP1 association, we overexpressed CrkL, ASAP1, or both in combination in COS7 cells. Unlike endogenous ASAP1 in platelets, overexpressed ASAP1 showed diffuse cytoplasmic distribution. However, when co-expressed with wild-type CrkL, both endogenous and expressed ASAP1 accumulated at CrkL-induced focal adhesions. An SH2-mutated CrkL, which cannot localize at focal adhesions, failed to recruit ASAP1 into focal adhesions. Thus, CrkL appears to be a lynchpin between ASAP1 and peripheral focal adhesions.

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JC virus agnoprotein colocalizes with tubulin.

Endo S, Okada Y, Orba Y, Nishihara H, Tanaka S, Nagashima K, Sawa H

Journal of neurovirology （TAYLOR & FRANCIS INC） 9 Suppl 1 10 - 14 2003年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1355-0284

The human polyomavirus JC (JCV) encodes an agnoprotein that consists of 71 amino acid residues, with a molecular weight of approximately 8 kDa, from the late protein coding region. The agnoprotein of JCV shares 50% to 60% homology with those of simian virus 40 (SV40) and BK virus (BKV), and the carboxyl-terminal region of JCV agnoprotein is relatively unique. By using specific antibody to the carboxyl-terminal region of JCV agnoprotein, the authors have demonstrated that JCV agnoprotein expressed in the JCV-infected cells, where it localized predominantly in the perinuclear region of the cytoplasm, and colocalizes with the cellular cytoskeletal protein, tubulin. The results suggest that JCV agnoprotein may play a role in the stability of microtubules and the preservation of JCV infected cells via an interaction with tubulin.

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DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines.

Nishihara H, Maeda M, Oda A, Tsuda M, Sawa H, Nagashima K, Tanaka S

Blood （12） 100 （ 12 ） 3968 - 3974 2002年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-4971

The CDM (ced-5 of Caenorhabditis elegans, DOCK180 [downstream of Crk with molecular weight of 180 kDa] of humans, and myoblast city of Drosophila melanogaster) family of proteins has been shown to play a pivotal role in the integrin-mediated signaling pathway under the regulation of an adaptor molecule c-CT10- related kinase II (c-Crk-II) in adherent cells. Recently, hematopoietic cell-specific CDM protein DOCK2 has been shown to be indispensable for lymphocyte migration. However, the regulatory mechanism for DOCK2 is still unknown because DOCK2 lacks a c-Crk-II binding consensus motif. In this study, we demonstrated that DOCK2 bound to CrkL, which is present exclusively in hematopoietic cells both in vivo and in vitro, and we also found that 2 separate regions of DOCK2 contributed to its binding to Src homology 3 (SH3) domain of CrkL. Colocalization of DOCK2 with Crk-like (CrkL) and F-actin was shown by immunocytochemical analysis with the use of Jurkat cells. We also found that CrkL-induced activation of small guanine triphosphatase (GTPase) Rac1 was significantly inhibited by the DOCK2-dCS mutant in 293T cells. Furthermore, the association of DOCK2 and Vav, the guanine-nucleotide exchanging factor (GEF) for Rac1, was demonstrated in Jurkat cells. Finally, the stable expression of DOCK2-dCS mutant in Jurkat cells was shown to reduce cell attachment. These data suggest the presence of a novel protein complex of CrkL, DOCK2, and Vav to regulate Rac1 in leukemia cell lines. (C) 2002 by The American Society of Hematology.

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Characterization of novel Alu- and tRNA-related SINEs from the tree shrew and evolutionary implications of their origins.

Nishihara H, Terai Y, Okada N

Molecular biology and evolution 19 （ 11 ） 1964 - 72 2002年11月

査読有り, ISSN 0737-4038

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Contrast-enhanced dynamic computed tomography for the evaluation of tumor angiogenesis in patients with lung carcinoma.

Tateishi U, Kusumoto M, Nishihara H, Nagashima K, Morikawa T, Moriyama N

Cancer （4） 95 （ 4 ） 835 - 842 2002年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0008-543X

BACKGROUND. The objective of this study was to investigate the role of contrast-enhanced dynamic computed tomography (CT) in the evaluation of tumor angiogenesis in patients with lung carcinoma and to assess its importance in predicting tumor size and lymph node involvement.
METHODS. Dynamic CT scans were evaluated retrospectively in 130 patients with primary lung carcinoma who did not have distant metastasis and who underwent surgical resection with mediastinal lymph node dissection. Histopathologic findings of vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) were correlated with the maximum attenuation values of time-attenuation curves (MAV) on dynamic CT scans.
RESULTS. The MAV in VEGF positive tumors was greater compared with the MAV in VEGF negative tumors (66.1 +/- 4.6 vs. 30.9 +/- 2.7, respectively; P < 0.0001). An association was found between the NUV in VEGF positive tumors and MVD (correlation coefficient = 0.650; P < 0.0001). No difference was found in tumor size with pathologic confirmation and the MAV, VEGF expression, or MVD. The MAV, VEGF expression, and MVD in lung tumors with lymph node involvement were greater compared with the same values in lung tumors without lymph node involvement.
CONCLUSIONS. The MAV of dynamic CT may be a predictor of tumor angiogenesis in patients with lung carcinoma and lymph node involvement. (C) 2002 American Cancer Society.

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DOCK2 mediates T cell receptor-induced activation of Rac2 and IL-2 transcription.

Nishihara H, Maeda M, Tsuda M, Makino Y, Sawa H, Nagashima K, Tanaka S

Biochemical and biophysical research communications （3） 296 （ 3 ） 716 - 720 2002年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0006-291X

DOCK2, a CDM family protein exclusively found in hematopoietic cells, has been shown to play a role in lymphocyte migration by the regulation of actin cytoskeleton. Although DOCK2 has been shown to induce the activation of Rac1, the regulatory mechanism of Rac2, which is a hematopoietic cell-specific small GTPase, is still unknown. In this study, we examined the role of DOCK2 in the activation of Rac2 in hematopoietic cells. DOCK2 was found to associate with the zeta subunit of the CD3 complex of T cell receptors in Jurkat cells and to activate forced expressed Rac2 in 293T cells. In addition, the stable expression of DOCK2 in Jurkat cells exhibited the elevated activity of endogenous Rac2. Furthermore, the transcriptional activity of interleukin-2 (IL-2) was enhanced in DOCK2-expressing Jurkat cells and the dominant negative form of Rac2 suppressed its elevated IL-2 promoter activity. These results suggest that DOCK2 mediates TCR-dependent activation of Rac2, leading to the regulation of IL-2 promoter activity in T cells. (C) 2002 Elsevier Science (USA). All rights reserved.

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Expression of JC virus agnoprotein in progressive multifocal leukoencephalopathy brain.

Okada Y, Sawa H, Endo S, Orba Y, Umemura T, Nishihara H, Stan AC, Tanaka S, Takahashi H, Nagashima K

Acta neuropathologica （2） 104 （ 2 ） 130 - 136 2002年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0001-6322

To examine the function of JC virus (JCV) agnoprotein, we examined the brains of cases of progressive multifocal leukoencephalopathy (PML), which is caused by JCV infection, using a newly generated antibody. The antibody reacted with 8 kDa protein specific for JCV agnoprotein by Western blotting. In vitro analyses showed that JCV capsid protein VP1 and large T antigen (T-Ag) were localized in the nuclei, but that agnoprotein was mainly detected in the cytoplasm of JCV-infected cells with an occasional nuclear staining. In the PML brain, an immunoreactive signal for agnoprotein was distributed in the perinuclear areas and cytoplasmic processes with occasional punctate staining in demyelinating lesions as well as adjacent myelinated areas. Agnoprotein presented mostly in the infected oligodendrocytes and partly in the astrocytes. Using double immunostaining, agnoprotein was seen to be expressed in the cytoplasmic processes of the cells, the nuclei of which were labeled with VP1 and T-Ag, where virus particles existed. Thus, JCV agnoprotein was mostly expressed in the infected oligodendrocytes and mainly localized in the cytoplasmic processes apart from virus particles in the demyelinated lesions.

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Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers.

Nishihara H, Tanaka S, Tsuda M, Oikawa S, Maeda M, Shimizu M, Shinomiya H, Tanigami A, Sawa H, Nagashima K

Cancer letters （1） 180 （ 1 ） 55 - 61 2002年06月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0304-3835

Crk is a signaling adaptor protein which is mostly composed of SH2 and SH3 domains. and has been shown to play a pivotal role in cell proliferation. differentiation, and migration. Because Crk was originally isolated as an avian sarcoma virus CT10 encoding oncoprotein v-Crk. we examined a potential role for c-Crk in the carcinogenesis of human cancers. First, to analyze gene mutations of c-Crk, we isolated a human bacterial artificial chromosome clone containing Crk genome and exon/intron structures, However, polymerase chain reaction-single strand conformation polymorphism methods failed to show any genomic mutations in the Crk exon which could be related to carcinogenesis. Second, immunohistochemical analysis of c-Crk-II demonstrated that the levels of c-Crk-II were significantly elevated in most of the tumors, particularly in the colon and lung cancers. Furthermore, immunoblot analysis using human lung cancer cell lines revealed that the expression levels of c-Crk-II were correlated to growth rates of L cells. The elevated expression levels of c-Crk-II might be related to the development of human cancers. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

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Lung tumors evaluated with FDG-PET and dynamic CT: the relationship between vascular density and glucose metabolism.

Tateishi U, Nishihara H, Tsukamoto E, Morikawa T, Tamaki N, Miyasaka K

Journal of computer assisted tomography （2） 26 （ 2 ） 185 - 190 2002年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0363-8715

Purpose: The aim of the current study was to evaluate the relationship between FDG-PET and dynamic CT in lung tumors.
Method: Forty consecutive patients with pulmonary tumors underwent whole-body FDG-PET and contrast-enhanced dynamic CT. The size of tumors was 2.6 +/- 0.2 cm (mean +/- SD) at the largest diameter. The standardized uptake value (SUV) of FDG-PET, peak attenuation (A(PA)), and relative flow (RF) of dynamic CT were evaluated. All patients underwent surgery. and tissue samples were available to be studied. The intratumoral microvessel densities (MVDs) were counted and compared with the radiologic parameters. The duration between radiologic examinations and surgery was within 2 weeks in all patients.
Results: The mean SUV, A(PA), and RF of lung cancers were significantly higher than those of benign lesions (p < 0.05). The mean A(PA) and RF of lung cancers correlated with mean SUV (A(PA) : r = 0.665, p < 0.0001: RF: r = 0.848, p < 0.05) and mean MVD (A(PA): r = 0.801, p < 0.0001; RF: r = 0.723, p < 0.05). The mean SUV of lung cancers correlated with the mean MVD (r = 0.612, p < 0.001). No correlation was found between the mean A(PA), RF, SUV, and MVD in benign tumors.
Conclusion: The A(PA) and RF of dynamic CT correlated with the SUV of FDG-PET imaging in lung cancer. The A(PA) and RF of dynamic CT as an index of blood pooling may be related to increased glucose metabolism in lung cancer.

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Solitary fibrous tumor of the pleura: MR appearance and enhancement pattern.

Tateishi U, Nishihara H, Morikawa T, Miyasaka K

Journal of computer assisted tomography （2） 26 （ 2 ） 174 - 179 2002年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0363-8715

Purpose: The aim of the current study was to characterize the MR appearance of solitary fibrous tumor of the pleura (SFTP).
Method: Twenty-two consecutive patients with histologically confirmed SFTP were retrospectively evaluated with MRI.
Results: Tumors demonstrated low signal intensity (n = 18, 82%). iso signal intensity (n = 2, 9%), and high signal intensity (n = 2. 9%) on T1-weighted images. On T2-weighted images, tumors were observed as low signal intensity (n = 10, 45%), high signal intensity (n = 2. 9%). and mixed signal intensity (n = 10, 45%). Solid component in the proliferation of tumor cells corresponded to low signal intensity in 12 tumors (55%) on T2-weighted images. On gadolinium-enhanced T1-weighted images, inhomogeneous enhancement (n = 18. 82%), nodular enhancement (n = 6, 27%), and homogeneous enhancement (n = 4, 18%) were observed. The enhanced lesion within the tumors had dense tumor tissue and dilated microvessels in the pathologic specimen.
Conclusion: SFTP shows variable appearance and enhancement pattern on MRI according to morphologic tumor heterogeneity.

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NM-1, a c-Myc-binding Protein, Is a Candidate for a Tumor Suppressor in Leukemia/Lymphoma and Tongue Cancer

Yuko Fujioka, Takahiro Taira, Yuichi Maeda, Shinya Tanaka, Hiroshi Nishihara, Sanae M. M. Iguchi-Ariga, Kazuo Nagashima, Hiroyoshi Ariga

Journal of Biological Chemistry 276 （ 48 ） 45137 - 45144 2001年11月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0021-9258

The c-myc oncogene product (c-Myc) is a transcription factor that dimerizes with Max and recognizes the E-box sequence, and it plays key functions in cell proliferation, differentiation, and apoptosis. We previously showed that MM-1 bound to myc box II within the transactivation domain of c-Myc and repressed the E-box-dependent transcriptional activity of c-Myc. Here we report that MM-1 showed features of a tumor suppressor. In an EST data base search for cDNAs homologous to MM-1, we found a frequent substitution of amino acid 157 of MM-1, from alanine to arginine (A157R), and the substitution was observed more in tumor cells than in normal cells. A survey of the A157R mutation of MM-1 in 57 cultured cancer cells and 90 tissues from cancer patients showed that the A157R was present in about 50-60% of leukemia/lymphoma cells and in more than 75% of squamous cell carcinoma of tongue cancer. Although both the A157R and the wild-type MM-1 bound to c-Myc, only A157R lost the activities to repress both the E-box-dependent transcriptional activity of c-Myc and the myc/ras cooperative transforming activity in rat 3Y1 cells. Furthermore, the wild-type MM-1, but not A157R, arrested the growth of 3Y1 cells. The human MM-1 gene was mapped at chromosome 12q12-12q13, where many chromosome abnormalities in cancer cells have been reported. The results suggest that MM-1 is a novel candidate for a tumor suppressor that controls the transcriptional activity of c-Myc.

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Broad distribution of the JC virus receptor contrasts with a marked cellular restriction of virus replication.

Suzuki S, Sawa H, Komagome R, Orba Y, Yamada M, Okada Y, Ishida Y, Nishihara H, Tanaka S, Nagashima K

Virology 286 （ 1 ） 100 - 12 2001年07月

ISSN 0042-6822

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HHV8-negative primary effusion lymphoma of the peritoneal cavity presenting with a distinct immunohistochemical phenotype.

Tanaka S, Katano H, Tsukamoto K, Jin M, Oikawa S, Nishihara H, Sawa H, Sawada K, Shimizu M, Sata T, Fujioka Y, Nagashima K

Pathology international 51 （ 4 ） 293 - 300 2001年04月

ISSN 1320-5463

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Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2

Nagai, M, Tanaka, S, Tsuda, M, Endo, S, Kato, H, Sonobe, H, Minami , A, Hiraga, H, Yamawaki, S, Nishihara, H, Sawa, H, Nagashima, K

Proc.Natl.Acad.Sci.USA （NATL ACAD SCIENCES） 98 （ 7 ） 3843 - 3848 2001年

研究論文（学術雑誌）, 共著, ISSN 0027-8424

Human synovial sarcoma has been shown to exclusively harbor the chromosomal translocation t(X;18) that produces the chimeric gene SYT-SSX. However, the role of SYT-SSX in cellular transformation remains unclear. In this study, we have established 3Y1 rat fibroblast cell lines that constitutively express SYT, SSX1, and SYT-SSX1 and found that SYT-SSX1 promoted growth rate in culture, anchorage-independent growth in soft agar, and tumor formation in nude mice. Deletion of the N-terminal 181 amino acids of SYT-SSX1 caused loss of its transforming activity. Furthermore, association of SYT-SSX1 with the chromatin remodeling factor hBRM/hSNF2 alpha, which regulates transcription, was demonstrated in both SYT-SSX1-expressing 3Y1 cells and in the human synovial sarcoma cell line HS-SY-II. The binding region between the two molecules was shown to reside within the N-terminal 181 amino acids stretch (aa 1-181) of SYT-SSX1 and 50 amino acids (aa 156-205) of hBRM/hSNF2 alpha and we found that the overexpression of this binding region of hBRM/hSNF2 alpha significantly suppressed the anchorage-independent growth of SYT-SSX1-expressing 3Y1 cells. To analyze the transcriptional regulation by SYT-SSX1, we established conditional expression system of SYT-SSX1 and examined the gene expression profiles. The down-regulation of potential tumor suppressor DCC was observed among 1,176 genes analyzed by microarray analysis, and semi-quantitative reverse transcription-PCR confirmed this finding. These data clearly demonstrate transforming activity of human oncogene SYT-SSX1 and also involvement of chromatin remodeling factor hBRM/hSNF2 alpha in human cancer.

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Clear cell variant of malignant melanoma of the uterine cervix: A case report and review of the literature

Mitsuko Furuya, Michio Shimizu, Hiroshi Nishihara, Tomoo Ito, Noriaki Sakuragi, Hiroshi Ishikura, Takashi Yoshiki

Gynecologic Oncology （Academic Press Inc.） 80 （ 3 ） 409 - 412 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0090-8258

Background. A rare variant of malignant melanoma of the uterine cervix mimicking clear cell carcinoma or clear cell sarcoma is described. Case. A 33-year-old Japanese woman was admitted to the hospital complaining of genital discharge and lower back pain. The stage was FIGO IIB and radical hysterectomy and pelvic lymphadenectomy were done. Pathological examination, immunohistochemical studies of melanin granules, and molecular analysis of the EWS/ATF-1 fusion gene were also done. A diffuse proliferation of amelanotic clear cells was detected in the uterine cervix. Tumor cells were positive for HMB 45, Melan-A (MART-1), and S-100 protein and negative for epithelial markers. The EWS/ATF-1 fusion gene was not detected. Conclusion. This is apparently the first report of a case of clear cell melanoma of the uterine cervix. Despite its rarity, this variant of malignant melanoma should be considered when diagnosing clear cell neoplasms of the uterine cervix. © 2001 Academic Press.

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HTLV-1-associated bronchopneumonopathy (HAB): CT-pathological correlation

Ukihide Tateishi, Hiroshi Nishihara, Kazuo Miyasaka

Clinical Radiology （Elsevier） 56 （ 8 ） 664 - 666 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9260

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