Shuji Matsubara

Kagawa University, Takamatu, Kagawa, Japan

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Publications (29)83.35 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We report an interesting case of a 47-yr-old who had a large goiter and multiple rib tumors. The patient was initially suspected of having thyroid cancer, which had metastasized on the ribs, based on imaging studies. However, laboratory tests revealed a high level of ionized calcium and parathyroid hormone (PTH). The large goiter was diagnosed as having parathyroid tumors owing to the high level of PTH in the tissue fluid. The biopsy specimen from a rib tumor was diagnosed as containing brown tumors associated with primary hyperparathyroidism (PHP). The patient also had prolactinoma and pancreatic gastrinoma. Her daughter had both prolactinoma and PHP, and her brother and her father had PHP. Thus, the patient was diagnosed as having multiple endocrine neoplasia type 1.
    Endocrine 04/2012; 12(1):11-14. DOI:10.1385/ENDO:12:1:11 · 3.88 Impact Factor
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    H Namihira · M Sato · K Murao · W M Cao · S Matsubara · H Imachi · M Niimi · H Dobashi · N C W Wong · T Ishida ·
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    ABSTRACT: Menin is a protein encoded by the gene mutated in multiple endocrine neoplasia type 1 (MEN1) characterized by multiple endocrine tumors of the parathyroid glands, pancreatic islets and the anterior pituitary, especially prolactinoma. In this study, we examined the effects of menin on human prolactin (hPRL) expression. In rat pituitary GH3 cells stably expressing menin, both PRL gene expression/secretion and thymidine incorporation into DNA were inhibited as compared with mock-transfected cells. The transcriptional activity of PRL promoter in GH3 cells co-transfected with menin was significantly decreased. A deletion mutation (569 delC), which we identified in a Japanese MEN1 family, was introduced into menin. When GH3 cells were transfected with a mutant menin expression vector, inhibition of hPRL promoter activity was partially reversed. These observations suggest that menin inhibits hPRL promoter activity and cell proliferation, raising the possibility that menin might play an important role in the tumorigenesis of prolactinoma.
    Journal of Molecular Endocrinology 01/2003; 29(3):297-304. · 3.08 Impact Factor
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    ABSTRACT: We report the case of a 24-yr-old man with a typical phenotype of multiple endocrine neoplasia type 2B (MEN 2B). The patient had previously undergone minor surgery to remove multiple tumors on the lip, but he had no further examinations. MEN 2B was suspected owing to characteristic multiple ganglioneuromatosis when the patient presented with a goiter associated with high levels of plasma calcitonin and CEA. Aspiration biopsy cytology revealed medullary thyroid carcinoma (MTC), and abdominal computed tomography and nuclear scanning with metaiodobenzylguanidine revealed bilateral adrenomedullary tumors. Adrenomedullary function tests showed high levels of serum and urinary fractionated catecholamines, and genetic analysis showed a point mutation in the codon 918 (M918T) of the RET gene. The patient was diagnosed with MEN 2B and underwent right adrenalectomy and total thyroidectomy. No distant metastasis of the MTC was noted although MEN 2B had remained undiagnosed since the ganglioneuromatosis was first noticed. MEN 2B is a rare hereditary disorder, but the occurrence of characteristic ganglioneuromatosis was quite helpful in making the diagnosis.
    Endocrine 08/2001; 15(2):143-6. DOI:10.1385/ENDO:15:2:143 · 3.88 Impact Factor
  • Makoto Sato · Shuji Matsubara · Koji Murao · Toshihiko Ishida · Jiro Takahara ·

    Internal Medicine 07/2001; 40(6):461-2. DOI:10.2169/internalmedicine.40.461 · 0.90 Impact Factor
  • X L Zheng · S Matsubara · C Diao · M D Hollenberg · N.C.W. Wong ·
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    ABSTRACT: Insulin induces apolipoprotein A-I, apoA-I gene transcription via a membrane receptor with intrinsic tyrosine kinase activity. This finding prompted us to ask whether the gene is stimulated by epidermal growth factor (EGF), EGF a peptide hormone that binds to another member of the receptor superfamily with tyrosine kinase activity. Our data showed that like insulin, EGF increased abundance of apoA-I protein and transcription of the gene in human hepatoma, Hep G2 cells. The effects of both hormones appeared direct because their induction of apoA-I gene transcription was not affected by the protein synthesis inhibitor, cycloheximide. Although both insulin and EGF stimulate apoA-I expression, each hormone binds to a distinct membrane receptor thus suggesting differential intracellular signaling. Therefore, we used a panel of inhibitors to define the pathway(s) that mediate the actions of these hormones. Whereas, the actions of EGF required only the Ras-mitogen-activated protein, MAP kinase, those of insulin were mediated by equal participation of both the Ras-MAP kinase and protein kinase C, PKC cascades. Despite differences in signaling pathways triggered by each hormone receptor, the activation of apoA-I transcription required the participation of a single transcription factor, Sp1. Furthermore, EGF induction of transcription was attenuated by mutating the MAP kinase site at amino acid, Thr(266) rendering Sp1 phosphorylation deficient. In summary, EGF stimulation of apoA-I expression is mediated solely by the Ras-MAP kinase cascade and enhanced activity of this pathway requires Sp1 with an intact phosphorylation site at Thr(266). However, insulin induction of this gene is different and requires both Ras-MAP kinase and PKC pathways but their actions are also mediated by Sp1.
    Journal of Biological Chemistry 05/2001; 276(17):13822-9. DOI:10.1074/jbc.M011031200 · 4.57 Impact Factor
  • X L Zheng · S Matsubara · C Diao · M D Hollenberg · N. C. W. Wong ·
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    ABSTRACT: Our previous finding that insulin induces apolipoprotein AI (apoAI) transcription points to the participation of intracellular signaling. This finding prompted us to ask whether two classical G-protein-coupled signaling pathways requiring activated protein kinase A (PKA) or kinase C (PKC) may also regulate apoAI. Therefore, human hepatoma, Hep G2 cells stably transfected with pAI.474-CAT, a reporter construct spanning -474 to -7 of apoAI DNA fused to chloramphenicol acetyltransferase (CAT) were treated with 10 microm forskolin (FSK) or 50 nm phorbol dibutyrate (PDBu) to activate PKA and PKC, respectively. Results showed that the apoAI promoter activity increased 4-5-fold following 24 h of treatment with either FSK or PDBu. Induction by either agent was blocked with actinomycin D but not the protein synthesis inhibitor, cycloheximide. The PKA inhibitor, PKI 14-22 amide, abrogated induction by FSK, 100 microm 8-bromo-cAMP, or 100 ng/ml cholera toxin, but it had no effect on activation via PKC. Similarly, PDBu induction was attenuated by 2 microm of the PKC inhibitor, GF109203X, but it did not affect FSK activity. Next we used deletional constructs to show that the actions of FSK and PDBu required the insulin-responsive core element (IRCE). This motif matched the consensus binding site for the transcription factor, Sp1. The binding of Sp1 to the IRCE was confirmed by gel-retardation and supershift analysis. Site-directed mutagenesis of the IRCE eliminated Sp1 action and induction by FSK or PDBu. Whereas overexpression of Sp1 enhanced basal and FSK or PDBu induced promoter activity, transfection of an antisense oligomer against Sp1 mRNA attenuated both parameters. In summary, activation of PKA or PKC increases apoAI promoter activity. The activity of both signaling pathways is mediated by the IRCE, a motif that binds the transcription factor, Sp1.
    Journal of Biological Chemistry 11/2000; 275(41):31747-54. DOI:10.1074/jbc.M000621200 · 4.57 Impact Factor
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    ABSTRACT: We report monozygotic twins who showed different MEN1 phenotypes. The proband (28 y.o., female) had both primary hyperparathyroidism (PHP) and insulinoma, and genetic analysis revealed a point mutation (569del1, exon 3) of the MEN1 gene. This mutation causes a frameshift and produces a stop codon at codon 184. Restriction digestion (HinfI) analysis confirmed the same mutation of the MEN1 gene in six of the affected members including her two sisters, the monozygotic twins, and no such mutation in two unaffected members. In two generations of this family, eight of eleven family members had PHP and four of them were found to have other MEN1-related lesions. Both of the monozygotic twins had PHP. Interestingly, one had pancreatic tumor but the other had no evidence of it. Pituitary MRI showed no pituitary lesion in either of them. This is the first Japanese case of monozygotic twins with different MEN1 phenotypes.
    Endocrine Journal 03/2000; 47(1):37-43. DOI:10.1507/endocrj.47.37 · 2.00 Impact Factor
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    ABSTRACT: The MEN1 gene has recently been cloned as the gene responsible for multiple endocrine neoplasia type 1 (MEN1) and its germline mutations have been identified in a number of familial MEN1 patients. However, mutation-negative cases have also been reported in some MEN1 families. We report here a Japanese MEN1 family, including a proband with no evidence of MEN1 gene mutation. The proband (51 y.o., female) had three major MEN1 lesions, including primary hyperparathyroidism (HP), prolactinoma, and pancreatic tumor. Her father and brother had HP, and her daughter had both HP and prolactinoma. When we analyzed the proband for a germline mutation of the MEN1 gene, the direct sequencing analysis showed no mutation in the coding region, on the promoter, 5' and 3' untranslated regions of the MEN1 gene. We next examined the loss of heterozygosity (LOH) in the proband's parathyroid tumors using two benign polymorphisms (C2249G in intron 1 and 2248del3 in exon 10) in the MEN1 gene to detect LOH. LOH was not found in any of the four separate regions of the tumor tissues.
    Endocrine Journal 01/2000; 46(6):811-6. DOI:10.1507/endocrj.46.811 · 2.00 Impact Factor
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    ABSTRACT: Familial multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder characterized by tumors of the parathyroid, anterior pituitary and gastro-entero-pancreatic endocrine tissues. The MEN1 gene has recently been cloned and its germline mutations have been considered to play an important role in the tumorigenesis of MEN1. We analyzed a Japanese MEN1 patient and her daughter for germline mutations of the MEN1 gene. The proband (60 y.o.) had primary hyperparathyroidism (PHP) and gastrinoma, and her daughter (30 y.o.) had prolactinoma. Clinical examinations revealed no evidence of PHP in the daughter. We identified a novel heterozygous germline mutation (712 A del) at codon 201 in exon 3 of the MEN1 gene in the proband. Restriction digestion analysis revealed the same mutation pattern in her daughter. These findings suggest that this family has familial MEN1 including a rare case of MEN1 with a single lesion of the pituitary. Genetic examinations are useful as diagnostic tools for any rare or variant case of familial MEN1.
    Endocrine Journal 05/1999; 46(2):325-9. DOI:10.1507/endocrj.46.325 · 2.00 Impact Factor
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    ABSTRACT: Familial primary hyperparathyroidism (FHP) is a rare hereditary disorder characterized by isolated parathyroid tumors without any other lesions related to multiple endocrine neoplasia (MEN). Primary hyperparathyroidism is usually expressed at an early age and is highly penetrated in MEN type 1 (MEN1), suggesting that some FHP may be a variant type or early stage of MEN1. The MEN1 gene has recently been cloned and its germline mutations have been considered to play an important role in the tumorigenesis of MEN1. We studied a Japanese family with primary hyperparathyroidism which included 4 patients. To investigate the possible relationship between primary hyperparathyroidism in this family and the MEN1 gene, we analyzed a proband for a germline mutation of the MEN1 gene in this study. We identified a novel heterozygous mutation (1350del3) at codon 414 in exon 9. Restriction digestion analysis revealed the same mutation pattern in his brother with hyperparathyroidism. These findings suggest that our patients may belong to a variant type of MEN1.
    Endocrine Journal 01/1999; 45(6):719-23. DOI:10.1507/endocrj.45.719 · 2.00 Impact Factor
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    ABSTRACT: The gene responsible for multiple endocrine neoplasia type 1 (MEN1) has recently been cloned, and its germline mutations were identified in patients with this syndrome. The majority of the mutations, frameshift or nonsense mutations, are expected to result in a loss of function of the gene product menin. Since the consequence of less common missense or in-frame deletion mutations is not clear, careful judgment is necessary regarding the role(s) of such mutations in MEN1 disease. Here we describe a large multigenerational MEN1 family with a novel germline missense mutation and three benign polymorphisms. The proband was a man with hyperparathyroidism and thymic carcinoid. We performed biochemical studies and DNA analyses of the MEN1 gene simultaneously and independently as family screening studies. Seven patients including the proband were identified, and all of them carried a heterozygous germline missense mutation E45G, but 5 members with normal biochemical results did not. This mutation was not observed in 50 normal volunteers. This novel missense mutation is therefore almost conclusively responsible for the disease. Although all of the mutant gene carriers in the present study already had clinical diseases, an MEN1 gene analysis in younger individuals at risk would be very useful in identifying carriers before the onset of the symptoms.
    Endocrine Journal 01/1999; 45(6):753-9. DOI:10.1507/endocrj.45.753 · 2.00 Impact Factor
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    M Sato · S Matsubara · A Miyauchi · H Ohye · H Imachi · K Murao · J Takahara ·
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    ABSTRACT: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroid glands, the anterior pituitary, and endocrine pancreas. The MEN1 gene has recently been cloned and germline mutations have been identified in MEN1 patients in the United States, Canada, and Europe. We examined MEN1 gene mutations in MEN1 and MEN1 related cases in eight unrelated Japanese families. These families include five familial MEN1 (FMEN1), two sporadic MEN1 (SMEN1), and one familial hyperparathyroidism (FHP). Direct sequence analysis of the protein coding regions was carried out in all the probands. We identified six different heterozygous mutations in the coding region, of which five were novel, including one missense mutation (E45G) in both FMEN1 and SMEN1, three deletions (569del, 711del, and 1350del3) in FMEN1 and FHP, and two nonsense mutations (R29X and Y312X) in FMEN1 and SMEN1. Only one of these mutations (Y312X) has previously been reported. One proband with FMEN1 had no mutation in the entire exon sequence including the 5' and 3' untranslated regions. A restriction digestion analysis of 19 relatives from the five families showed a close correlation between the existence of the MEN1 gene mutation and disease onset. Four different polymorphisms, including two novel ones, were identified. These findings imply that a diversity of MEN1 gene mutations exists in Japanese MEN1 and MEN1 related disease, suggesting that analysis of the entire coding region of the MEN1 gene is required for genetic counselling in Japan.
    Journal of Medical Genetics 12/1998; 35(11):915-9. DOI:10.1136/jmg.35.11.915 · 6.34 Impact Factor
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    ABSTRACT: We identified a novel nonsense mutation(R29X) of the MEN1 gene in a familial multiple endocrine neoplasia type 1 (MEN1) patient. Molecular analysis of the MEN1 gene was performed in the family members by a restriction digestion method. The same mutation pattern was seen in both the proband's younger brother and cousin diagnosed as MEN1, and was also observed in the son of the cousin who showed signs of normal levels of serum PTH associated with mild hypercalcemia and hypophosphatemia. These findings suggest that mutation analysis of the MEN1 gene is very useful in identifying the subclinical state of MEN1 as well as clinical MEN1.
    Endocrine Journal 11/1998; 45(5):653-7. DOI:10.1507/endocrj.45.653 · 2.00 Impact Factor
  • Hidemi Ohye · Makoto Sato · Koji Murao · Shuji Matsubara · Masaaki Tokuda · Jiro Takahara ·
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    ABSTRACT: Although an immunosuppressant, FK506, has been known to stimulate growth hormone (GH) release from rat somatotropes, the cellular signaling mechanism is unknown. In the present study, intracellular signaling pathways were investigated for FK506- and cyclosporin A (CsA)-induced GH release in cultured rat anterior pituitary cells. Northern and Western blot analysis revealed that the FK506-binding protein (FKBP12) and the CsA-binding protein (cyclophilin A) exist at the mRNA and protein level in the rat anterior pituitary tissue. FK506 and CsA increased GH release in a dose-dependent manner and inhibited calcineurin (CaN) activity in the cultured pituitary cells. The third immunosuppressant, rapamycin (RP), inhibited the FK506-induced GH release, although RP alone had no effect. Protein kinase A (PKA) inhibitors, H-89 and HA-1004 and EGTA blocked FK506- and CsA-induced GH release. TGF-beta did not alter basal GH release, but inhibited FK506-induced GH release. GH primary transcripts were increased by FK506, and the effects were blocked by H-89 and HA-1004. These results suggest that the immunosuppressants, FK506 and CsA, stimulate GH release by inhibiting CaN activity which results in the activation of the PKA system in the rat somatotropes. TGF-beta receptors might be involved in FK506-induced GH release as a separate pathway. FK506 also stimulates GH primary transcripts via a PKA-dependent mechanism in a manner similar to its effects on GH release.
    NeuroImmunoModulation 10/1998; 5(6):309-17. DOI:10.1159/000026350 · 1.88 Impact Factor
  • Hidemi Ohye · Makoto Sato · Shuji Matsubara · Tomoyo Ohyama · Koji Murao · Jiro Takahara ·

    Endocrine Journal 05/1998; 45 Suppl(Suppl):S93-6. DOI:10.1507/endocrj.45.Suppl_S93 · 2.00 Impact Factor
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    ABSTRACT: We cloned a fragment of the rat GH-releasing peptide (GHRP) receptor homologue and examined the tissue distribution of GHRP receptor mRNA in rats. Sequence analysis showed that the open reading frame is well conserved between rat and human with 96% identity in a 364-amino acid overlap. By reverse transcription-polymerase chain reaction we detected GHRP receptor mRNAs in the rat brain including the hypothalamus, anterior pituitary, and renal pelvis in twenty-eight tissues tested. Microdissection revealed that GHRP receptor mRNAs were localized predominantly in the arcuate nucleus and ventromedial hypothalamus.
    Peptides 02/1998; 19(1):15-20. DOI:10.1016/S0196-9781(97)00263-5 · 2.62 Impact Factor
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    Shuji Matsubara · Makoto Sato · Hidemi Ohye · Koji Murao · Jiro Takahara ·
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    ABSTRACT: We have developed a novel method of quantifying growth hormone(GH) pre-mRNA expression in anterior pituitary cells. DNA-free total RNA extracted from cultured rat anterior pituitary cells was reverse transcribed(RT) to cDNA, and RT products were subsequently quantitated by competitive PCR using intron-specific primers of rat GH gene. After 6-h of incubation in treated cells, dexamethasone(Dex) and triiodo-L-thyronine(T3) significantly increased GH pre-mRNA levels(3.2- and 2.2-fold compared to non-treated cells, respectively). However, Northern blot analysis did not detect significant changes in GH mRNA levels. After 24-h incubation with Dex and T3, significant increases in GH mRNA levels were detected on Northern blots, but GH pre-mRNA levels did not differ between treated and non-treated cells. These findings suggest that both Dex and T3 treatments rapidly increase GH pre-mRNA levels in normal somatotropes. This method has high sensitivity and widespread application to the analysis of pre-mRNAs of target genes.
    Endocrinology 12/1997; 138(11):5075-8. DOI:10.1210/en.138.11.5075 · 4.50 Impact Factor
  • M Nagai · M Fujita · M Ohmori · S Matsubara · M Taniwaki · S Horiike · T Tasaka · H P Koeffler · J Takahara ·
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    ABSTRACT: The novel human pre-B cell line OZ was established from a patient with an aggressive form of non-Hodgkin's lymphoma. Karyotypic analysis of both the primary tumour and OZ cells revealed several marker chromosomes, including the t(14;18)(q32;q21) translocation, which involves the Bcl-2 gene, and alterations on chromosome 17p. Southern blot analysis found identical rearrangements in the 5' region of Bcl-2 gene in the primary tumour and OZ cells. Homozygous deletions of the p15INK4B and p16INK4A genes, however, were present only in OZ cells. Western blot analysis detected aberrant small molecular-weight p53 proteins in both cell types. In addition, OZ cells no longer expressed the CD20 antigen. These findings suggest that Bcl-2 gene rearrangement and aberrant p53 expression resulted in the original B-cell tumour. A subsequent transforming event involving the p15INK4B and p16INK4A genes may have generated more immature cells with a growth advantage during in vitro culture. The genetic alterations involving p53, p15INK4B, and p16INK4A may be implicated in the aggressive form of t(14;18)(q32;q21)-bearing tumours and their poor prognosis.
    Hematological Oncology 09/1997; 15(3):109-19. DOI:10.1002/(SICI)1099-1069(199708)15:33.0.CO;2-Y · 3.08 Impact Factor
  • Tomoyo Ohyama · Makoto Sato · Hidemi Ohye · Shuji Matsubara · Jiro Takahara ·

    Clinical Pediatric Endocrinology 01/1997; 6(Supple9):81-83. DOI:10.1297/cpe.6.Supple9_81
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    S Matsubara · Y Yamaji · M Sato · J Fujita · J Takahara ·
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    ABSTRACT: Recently, a photoreceptor protein, recoverin, has been recognised as an autoantigen of cancer-associated retinopathy (CAR), a rare paraneoplastic neurological syndrome often associated with patients with small-cell lung cancer (SCLC). Although until quite recently the specific expression of recoverin in cancer cells had not been indicated, Polans et al. (Polans AS, Witkowska D, Haley TL, Amundson D, Baizer L, Adamus G 1995, Proc. Natl. Acad. Sci. USA, 92, 9176-9180) demonstrated the specific expression of recoverin in lung tumour and primary cultured tumour cells from a CAR patient. We examined the expression of recoverin in human lung cancer cell lines by reverse transcription polymerase chain reaction (PCR), Northern blotting and Western immunoblotting. Recoverin was expressed in only one SCLC cell line from a patient with CAR. The sequence of recoverin cDNA from the cells was identical to the human recoverin sequence. These findings strongly support the hypothesis that the ectopic expression of wild-type recoverin in SCLC induces the cancer-retina immunological cross-reaction, leading to visual loss in CAR. Images Figure 1 Figure 2 Figure 3
    British Journal of Cancer 12/1996; 74(9):1419-22. DOI:10.1038/bjc.1996.558 · 4.84 Impact Factor

Publication Stats

557 Citations
83.35 Total Impact Points


  • 1997-2012
    • Kagawa University
      • Faculty of Medicine
      Takamatu, Kagawa, Japan
  • 1999
    • Kuma Hospital
      Kōbe, Hyōgo, Japan
  • 1995
    • Hamamatsu Minami Hospital
      Hamamatu, Shizuoka, Japan