Miyuki Shimane

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (30)149.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung adenocarcinoma is heterogeneous regarding histology, etiology and prognosis. Although there have been several attempts to find a subgroup with poor prognosis, it is unclear whether or not adenocarcinoma with neuroendocrine (NE) nature has unfavorable prognosis. To elucidate whether a subtype of adenocarcinoma with NE nature has poor prognosis, we performed gene expression profiling by cDNA microarray for 262 Japanese lung cancer and 30 normal lung samples, including 171 adenocarcinomas, 56 squamous cell carcinomas and 35 NE tumors. A co-expression gene set with ASCL1, an NE master gene, was utilized to classify tumors by non-negative matrix factorization, followed by validation using an ASCL1 knock-down gene set in DMS79 cells as well as an independent cohort (n=139) derived from public microarray databases as a test set. The co-expression gene set classified the adenocarcinomas into alveolar cell (AL), squamoid, and NE subtypes. The NE subtype, which clustered together almost all the NE tumors, had significantly poorer prognosis than the AL subtype that clustered with normal lung samples (p=0.0075). The knock-down gene set also classified the 171 adenocarcinomas into three subtypes and this NE subtype also had the poorest prognosis. The co-expression gene set classified the independent database-derived American cohort into two subtypes, with the NE subtype having poorer prognosis. None of the single NE gene expression was found to be linked to survival difference. Co-expression gene set with ASCL1, rather than single NE gene expression, successfully identifies an NE subtype of lung adenocarcinoma with poor prognosis.
    Lung cancer (Amsterdam, Netherlands) 07/2011; 75(1):119-25. DOI:10.1016/j.lungcan.2011.05.028 · 3.74 Impact Factor
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    ABSTRACT: The Philadelphia chromosome-positive blastoma, maintained by serial subcutaneous transplantation in nude mice, is a highly proliferating biological mass consisting of homogenous CD34(+)CD38(-) myeloblastoid cells. These cells newly evolved from pluripotent leukemia stem cells of chronic myeloid leukemia in the chronic phase. Therefore, this mass may provide a unique tool for better understanding cellular and molecular mechanisms of self-renewal of leukemia stem cells. In this paper, we demonstrated that intravenously injected blastoma cells can cause Ph+ blastic leukemia with multiple invasive foci in NOD/SCID mice but not in nude mice. In addition, using an in vitro culture system, we clearly showed that blastoma cell adhesion to OP9 stromal cells accelerates blastoma cell proliferation that is associated with up-regulation of BMI1 gene expression; increased levels of beta-catenin and the Notch1 intra-cellular domain; and changed the expression pattern of variant CD44 forms, which are constitutively expressed in these blastoma cells. These findings strongly suggest that adhesion of leukemic stem cells to stromal cells via CD44 might be indispensable for their cellular defense against attack by immune cells and for maintenance of their self-renewal ability.
    Biochemical and Biophysical Research Communications 03/2010; 396(2):193-8. DOI:10.1016/j.bbrc.2010.03.172 · 2.28 Impact Factor
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    ABSTRACT: For long-term survival in vitro and in vivo of acute myeloid leukemia cells, their adhesion to bone marrow stromal cells is indispensable. However, it is still unknown if these events are uniquely induced by the leukemic stem cells. Here we show that TF-1 human leukemia cells, once they have formed a cobblestone area by adhering to mouse bone marrow-derived MS-5 cells, can acquire some leukemic stem cell like properties in association with a change in the CD44 isoform-expression pattern and with an increase in a set of related microRNAs. These findings strongly suggest that at least some leukemia cells can acquire leukemic stem cell like properties in an adhesion-mediated stochastic fashion.
    Biochemical and Biophysical Research Communications 02/2010; 392(3):271-6. DOI:10.1016/j.bbrc.2009.12.163 · 2.28 Impact Factor
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    ABSTRACT: The co-culture of TF-1 leukemia cells and MS-5 stromal cells produces a cobblestone area which partially mimics the leukemia stem cell niche. The adhering leukemia cells are shown to become less sensitive to cytarabine, etoposide and daunorubicin. These changes are associated with an increased proportion of the G0/G1 phase, increased upregulation of cyclin-dependent kinase inhibitors, and increased levels of Bcl-2, but not with any change in the expression of BAX or drug transporters such as ABCG2 and MDR1, compared to monocultured leukemic cells. In addition, we demonstrate using a bioimaging technique that daunorubicin accumulates in the lysosomes of the adherent leukemic cells and that V-ATPase is activated. These findings suggest that adhesion alone can lead to drug resistance in leukemic stem cells by various mechanisms.
    Pharmacology 01/2010; 86(2):79-84. DOI:10.1159/000305344 · 1.58 Impact Factor
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    ABSTRACT: To investigate the molecular mechanism of endometriosis, gene expression profiling was analyzed in a rat endometriosis model. An endometriosis model was induced by uterine autotransplantation in the peritoneal cavity on a female-SD rat (8 weeks old). As control samples, the normal uterine tissues were used. The gene expression was compared between endometriotic lesions and normal uterine tissues by cDNA microarray analysis, quantitative real time RT-PCR and immunohistochemistry. The expression of 71 genes was upregulated and that of 45 genes was downregulated in the endometriotic lesions compared to normal uterine tissues. The upregulated genes included genes encoding cytokines, chemokines, growth factors and cell adhesion molecules. The levels of transcripts of osteopontin, Lyn, Vav1, Runx1, and l-selectin in the endometriotic lesions were 130, 10, 10, 12 and 46-fold higher than the respective levels in the eutopic endometrial samples. The results suggest that osteopontin, Lyn, Vav1, Runx1, and l-selectin play important roles in the pathogenesis of endometriosis.
    American journal of reproductive immunology (New York, N.Y.: 1989) 11/2007; 58(4):330-43. DOI:10.1111/j.1600-0897.2007.00507.x · 2.67 Impact Factor
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    ABSTRACT: Current clinical and histopathological criteria used to define lung squamous cell carcinomas (SCCs) are insufficient to predict clinical outcome. To make a clinically useful classification by gene expression profiling, we used a 40 386 element cDNA microarray to analyse 48 SCC, nine adenocarcinoma, and 30 normal lung samples. Initial analysis by hierarchical clustering (HC) allowed division of SCCs into two distinct subclasses. An additional independent round of HC induced a similar partition and consensus clustering with the non-negative matrix factorization approach indicated the robustness of this classification. Kaplan-Meier analysis with the log-rank test pointed to a nonsignificant difference in survival (P = 0.071), but the likelihood of survival to 6 years was significantly different between the two groups (40.5 vs 81.8%, P = 0.014, Z-test). Biological process categories characteristic for each subclass were identified statistically and upregulation of cell-proliferation-related genes was evident in the subclass with poor prognosis. In the subclass with better survival, genes involved in differentiated intracellular functions, such as the MAPKKK cascade, ceramide metabolism, or regulation of transcription, were upregulated. This work represents an important step toward the identification of clinically useful classification for lung SCC.
    Oncogene 11/2005; 24(47):7105-13. DOI:10.1038/sj.onc.1208858 · 8.56 Impact Factor
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    ABSTRACT: The utility of cancer cell lines depends largely on their accurate classification, commonly based on histopathological diagnosis of the cancers from which they were derived. However, because cancer is often heterogeneous, the cell line, which also has the opportunity to alter in vitro, may not be representative. Yet without the overall architecture used in histopathological diagnosis of fresh samples, reclassification of cell lines has been difficult. Gene-expression profiling accurately reproduces histopathological classification and is readily applicable to cell lines. Here, we compare the gene-expression profiles of 41 cell lines with 44 tumors from lung cancer. These profiles were generated after hybridization of samples to four replicate 7,685-element cDNA microarrays. After removal of genes that were uniformly up- or down-regulated in fresh compared with cell-line samples, cluster analysis produced four major branch groups. Within these major branches, fresh tumor samples essentially clustered according to pathological type, and further subclusters were seen for both adenocarcinoma (AC) and small cell lung carcinoma (SCLC). Four of eight squamous cell carcinoma (SCC) cell lines clustered with fresh SCC, and 11 of 13 SCLC cell lines grouped with fresh SCLC. In contrast, although none of the 11 AC cell lines clustered with AC tumors, three clustered with SCC tumors and six with SCLC tumors. Although it is possible that preexisting SCC or SCLC cells are being selected from AC tumors after establishment of cell lines, we propose that, even in situ, AC will ultimately progress toward one of two poorly differentiated phenotypes with expression profiles resembling SCC or SCLC.
    Proceedings of the National Academy of Sciences 10/2002; 99(19):12357-62. DOI:10.1073/pnas.192240599 · 9.81 Impact Factor
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    ABSTRACT: Peutz-Jeghers syndrome (PJS) is a dominantly inherited human disorder characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. LKB1 (STK11) serine/threonine kinase is the product of the causative gene of PJS, which has been mapped to chromosome 19p13.3. However, several studies have produced results that are not consistent with a link between LKB1 gene mutation and PJS. We constructed a knockout gene mutation of Lkb1 to determine whether it is the causative gene of PJS and to examine the biological role of the Lkb1 gene. Lkb1(-/-) mice died in utero between 8.5 and 9.5 days postcoitum. At 9.0 days postcoitum, Lkb1(-/-) embryos were generally smaller than their age-matched littermates, showed developmental retardation, and did not undergo embryonic turning. Multiple gastric adenomatous polyps were observed in 10- to 14-month-old Lkb1(+/-) mice. Our results indicate that functional Lkb1 is required for normal embryogenesis and that it is related to tumor development. The Lkb1(+/-) mouse is suitable for studying molecular mechanism underlying the development of inherited gastric tumors in PJS.
    Proceedings of the National Academy of Sciences 07/2002; 99(13):8903-8. DOI:10.1073/pnas.122254599 · 9.81 Impact Factor
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    ABSTRACT: OCTN2 is an Na(+)-dependent transporter for carnitine, which is essential for fatty acid metabolism, and its functional defect leads to fatal systemic carnitine deficiency (SCD). It also transports the organic cation tetraethylammonium (TEA) in an Na(+)-independent manner. Here, we studied the multifunctionality of OCTN2, by examining the transport characteristics in cells transfected with mouse OCTN2 and in juvenile visceral steatosis (jvs) mice that exhibit a SCD phenotype owing to mutation of the OCTN2 gene. The physiological significance of OCTN2 as an organic cation transporter was confirmed by using jvs mice. The embryonic fibroblasts from jvs mice exhibited significantly decreased transport of [(14)C]TEA. Pharmacokinetic analysis of [(14)C]TEA disposition demonstrated that jvs mice showed decreased tissue distribution and renal secretory clearance. In transport experiments using OCTN2-expressing cells, TEA and carnitine showed mutual trans-stimulation effects in their transport, implying a carnitine/TEA exchange mechanism. In addition, Na(+) affected the affinity of carnitine for OCTN2, whereas Na(+) is unlikely to be involved in TEA transport. This is the first molecular and physiological demonstration of the operation of an organic cation transporter in renal apical membrane. The results are consistent with the physiological coupling of carnitine reabsorption with the secretion of organic cations.
    Molecular Pharmacology 03/2001; 59(2):358-66. · 4.12 Impact Factor
  • 01/2001; 16(2):127-133. DOI:10.2133/dmpk.16.127
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    ABSTRACT: Carnitine is essential for beta-oxidation of fatty acids, and a defect of cell membrane transport of carnitine leads to fatal systemic carnitine deficiency. We have already shown that a defect of the organic cation/carnitine transporter OCTN2 is a primary cause of systemic carnitine deficiency. In the present study, we further isolated and characterized new members of the OCTN family, OCTN1 and -3, in mice. All three members were expressed commonly in kidney, and OCTN1 and -2 were also expressed in various tissues, whereas OCTN3 was characterized by predominant expression in testis. When their cDNAs were transfected into HEK293 cells, the cells exhibited transport activity for carnitine and/or the organic cation tetraethylammonium (TEA). Carnitine transport by OCTN1 and OCTN2 was Na(+)-dependent, whereas that by OCTN3 was Na(+)-independent. TEA was transported by OCTN1 and OCTN2 but not by OCTN3. The relative uptake activity ratios of carnitine to TEA were 1.78, 11.3, and 746 for OCTN1, -2, and -3, respectively, suggesting high specificity of OCTN3 for carnitine and significantly lower carnitine transport activity of OCTN1. Thus, OCTN3 is unique in its limited tissue distribution and Na(+)-independent carnitine transport, whereas OCTN1 efficiently transported TEA with minimal expression of carnitine transport activity and may have a different role from other members of the OCTN family.
    Journal of Biological Chemistry 01/2001; 275(51):40064-72. DOI:10.1074/jbc.M005340200 · 4.60 Impact Factor
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    ABSTRACT: We identified three novel transporters structurally belonging to the organic anion transporting polypeptide (OATP) family in humans. Since previously known rat oatp1 to 3 do not necessarily correspond to the human OATPs in terms of either tissue distribution or function, here we designate the newly identified human OATPs as OATP-B, -D and -E, and we rename the previously known human OATP as OATP-A. OATP-C proved to be identical with the recently reported LST1/OATP-2. Expression profiles of the five OATPs and the prostaglandin transporter PGT (a member of OATP family) in human tissues showed that OATP-C is exclusively localized in liver, OATP-A and PGT are expressed in restricted ranges of tissues, and OATP-B, -D and -E show broad expression profiles. OATP-B, -C, -D and -E exhibited transport activity for [(3)H]estrone-3-sulfate as a common substrate. OATP-C has a high transport activity with broad substrate specificity.
    Biochemical and Biophysical Research Communications 07/2000; 273(1):251-60. DOI:10.1006/bbrc.2000.2922 · 2.28 Impact Factor
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    ABSTRACT: LKB1 serine/threonine kinase is a gene for Peutz-Jeghers cancer pre- disposition syndrome. Most studies have detected a low frequency of LKB1 defects in sporadic cancer. A notable exception is a recent report describ- ing frequent, mostly missense type, LKB1 mutations in Korean distal colorectal tumors. To clarify the role of LKB1 in colon cancer, we scru- tinized 50 left-sided Korean and Finnish specimens. No somatic mutations were found. The seven Korean somatic missense mutations reported previously were functionally analyzed, and five were found not to alter LKB1 kinase activity. One of these changes was found to be a germ-line polymorphism. LKB1 involvement in distal colorectal cancer is not com- mon.
    Cancer Research 03/2000; 60(3). · 9.28 Impact Factor
  • Michael H. Jones, Naeko Hamana, Miyuki Shimane
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    ABSTRACT: The bromodomain is a 110-amino-acid conserved structural region associated with proteins that regulate signal-dependent, nonbasal transcription. The bromodomain can regulate histone acetyl transferase activity and interacts specifically with acetylated lysine residues. A key role for bromodomain proteins in maintaining normal proliferation is indicated by the implication of several bromodomain proteins in cancer, with four of these identified at translocation breakpoints. We searched EST databases for novel bromodomain genes. The sequence from one EST was used to initiate generation of a full-length clone from a testis cDNA library. The completed sequence encodes a predicted protein of 2781 amino acids, which, in addition to the bromodomain, harbors further motifs characteristic of a transcriptional coactivator: two PHD fingers and an extensive glutamine-rich acidic domain. There are several other regions that are conserved with the Caenorhabditis elegans putative protein F26H11, which may be functionally homologous. The novel gene, called BPTF, is expressed in all tissues examined as a 10.5-kb transcript. The protein has extensive identity with the smaller FAC1 protein, suggesting that the two either are derived from the same locus or are synonymous. BPTF has been mapped to 17q23. Functional domains found within BPTF are consistent with a role for this protein in hormonally regulated, chromatin-mediated regulation of transcription.
    Genomics 02/2000; 63(1):35-9. DOI:10.1006/geno.1999.6070 · 2.79 Impact Factor
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    ABSTRACT: The bromodomain is a structural motif characteristic of proteins involved in chromatin-dependent regulation of transcription. Bromodomain proteins have been identified as integral components of chromatin remodeling complexes and frequently possess histone acetyltransferase activity. Their encoding genes have been identified at translocation breakpoints, and at least one, CBP, is a tumor suppressor gene. We have identified a series of novel bromodomain genes by EST database and cDNA library screening. Comparison of sequences for four clones indicated that they represent genes belonging to a novel bromodomain family. Full-length sequences for these genes, which are widely expressed, predict encoded proteins of between 1527 and 1972 amino acids. In addition to a carboxy-terminal bromodomain, an adjacent PHD finger, and a WACZ motif, at least four other conserved novel motifs are present in each protein. The genes contain regions conserved with Drosophila Acf1 and Caenorhabditis elegans ZK783.4. The novel genes, termed BAZ1A, BAZ1B, BAZ2A, and BAZ2B, localize to chromosomes 14q12-q13, 7q11-q21, 12q24.3-qter, and 2q23-q24, respectively. Conservation of multiple domains throughout these genes with Acf1 indicates that they are likely to be components of chromatin remodeling complexes.
    Genomics 02/2000; 63(1):40-5. DOI:10.1006/geno.1999.6071 · 2.79 Impact Factor
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    ABSTRACT: We identified and characterized novel Na+-dependent carnitine/organic cation transporter family, OCTNs from human and mouse. We isolated two and three members of OCTN family from human and mouse, respectively. OCTNs are present in various tissues, including kidney, heart, skeletal muscle and placenta strongly, and in several human-derived cancer cell lines. By immunohistochemical analysis in kidney, mouse OCTNs localized commonly in luminal membrane of tubular epithelial cells. Most of human and mouse OCTNs exhibited multifunctionality by transporting both of carnitine and organic cation, tetraethylammonium (TEA). Furthermore, sodium ions were essential for carnitine transport by human and mouse OCTN1 and 2. In systemic carnitine deficiency (SCD) phenotype mouse model, juvenile visceral steotosis (jvs) mouse, mutation in OCTN2 gene was found. Furthermore, several kinds of mutation in human SCD patients were found, demonstrating that OCTN2 is a physiologically important carnitine transporter. Interestingly, TEA transport was sodium independent. In addition, OCTNs transporterd various cationic drugs such as quinidine, verapamil, and actinomycin D. Furthermore, since one mutation of human OCTN2 lost carnitine transport activity but retained TEA transport activity, it was suggested that OCTN2 have differential functional sites for carnitine and organic cations. So, OCTNs are thought to be multifunctional transporters by transporting carnitine and organic cations by sodium ion dependent and independent manner, respectively, and would be important for disposition of organic cationic drugs as well as carnitine.
    01/2000; 15(2):182-188. DOI:10.2133/dmpk.15.182
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    ABSTRACT: Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder of fatty acid oxidation caused by defective cellular carnitine transport. The disease is characterized by metabolic derangement simulating Reye's syndrome, hypoglcaemia, progressive cardiomyopathy and skeletal myopathy. Recently, it was shown that SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5). We report two novel mutations, W283R and V446F, which are both missense mutations in an affected infant. In vitro expression studies demonstrated that both are actually function-loss mutations with virtually no uptake activity. This is the first report of compound heterozygosity for two missense mutations in a patient with SCD. Hum Mutat 15:118, 2000.
    Human Mutation 01/2000; 15(1):118. DOI:10.1002/(SICI)1098-1004(200001)15:1<118::AID-HUMU28>3.0.CO;2-8 · 5.05 Impact Factor
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    ABSTRACT: Carnitine deficiency, either primary or drug-induced, causes critical symptoms and is thought to involve alteration of active transport of carnitine across the plasma membrane of tissues as the underlying mechanism. Recently, we showed that human organic cation transporter, hOCTN2, cloned as a member of the organic cation transporter family, is a physiologically important Na(+)-dependent high-affinity carnitine transporter in humans. In this study, we further characterized the functional properties of hOCTN2 and examined the interaction between hOCTN2-mediated carnitine transport and clinically used drugs to assess possible toxicological effects. When expressed in human embryonic kidney (HEK)293 cells, hOCTN2 showed low but significant stereospecific transport activity: D-carnitine was transported with lower affinity (K(m) = 10.9 microM) than the L-isomer (K(m) = 4.3 microM). One Na(+) appeared to be associated with the transport of one carnitine molecule. hOCTN2-mediated transport of acetyl-L-carnitine was also Na(+)-dependent and of high affinity, with a K(m) value of 8.5 microM. To examine the transport activity for organic cations other than carnitine and the possible relationship of drug-induced carnitine deficiency with hOCTN2, the inhibitory effect of several drugs on hOCTN2-mediated L-carnitine transport was examined. Many zwitterionic drugs, such as cephaloridine, and many cationic drugs, such as quinidine and verapamil, exhibited significant inhibitory effects. Among these inhibitors, tetraethylammonium, pyrilamine, quinidine, verapamil, and valproate were found to be transported by hOCTN2. The results suggest that the carnitine deficiency-related toxicological effects by long-term treatment with such drugs might be ascribed to a functional alteration of hOCTN2-mediated carnitine transport.
    Journal of Pharmacology and Experimental Therapeutics 12/1999; 291(2):778-84. · 3.86 Impact Factor
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    ABSTRACT: Juvenile visceral steatosis (JVS) mice, which show systemic L-carnitine deficiency, may be an animal model of Reye's syndrome because of its phenotype of fat deposition and mitochondrial abnormalities in the liver. In this study, we compared the characteristics of the L-carnitine transport in isolated hepatocytes from wild-type and JVS mice. The uptake of L-carnitine by wild-type hepatocytes was saturable and the Eadie-Hofstee plot showed 2 distinct components. The apparent Michaelis constant (K(m)) and the maximum transport rate (V(max)) were 4.6 micromol/L and 59.5 pmol/15 min/10(6) cells, respectively, for the high-affinity component, and 404 micromol/L and 713 pmol/15 min/10(6) cells, respectively, for the low-affinity component. The high-affinity L-carnitine uptake occurred via an active carrier-mediated transport mechanism, which is characterized by Na(+)-, energy-, and pH-dependency. On the other hand, the high-affinity uptake was absent in JVS hepatocytes, and the values of K(m) and V(max) for the low-affinity uptake were 475 micromol/L and 557 pmol/15 min/10(6) cells, respectively. The hepatic carnitine transport properties in wild-type hepatocytes were similar to those of high-affinity mouse Octn2-transfected HEK293 cells. This study suggests that Octn2-type carnitine transporter is dysfunctional in hepatocytes of JVS mice.
    Hepatology 10/1999; 30(4):997-1001. DOI:10.1002/hep.510300423 · 11.19 Impact Factor
  • Jun-ichi Nezu, Asuka Oku, Miyuki Shimane
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    ABSTRACT: LKB1 Serine/Threonine (ST) kinase (also called STK11) originally identified in our novel protein kinase search project has recently been recognized as a susceptibility gene of Peutz-Jeghers Syndrome (PJS; MIM 175200). PJS is a dominantly inherited human disorder which is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. Since PJS patients also show a predisposition to a wide spectrum of cancers, it is speculated that LKB1 has a tumor suppressor function. In the present study we have characterized the basic biochemical property of LKB1. In the analysis of mutant LKB1 identified in PJS patients, it was found that one of the mutants, SL26, does not lose its kinase function, but alters its subcellular distribution to accumulate in the nucleus only, whereas wild type LKB1 shows both nuclear and cytoplasmic localization. Domain mapping of the nuclear targeting signal of LKB1 assigned it to its amino terminal side. Furthermore, it was shown that LKB1 also has a cytoplasmic retention ability which is considered defective and pathogenic in the SL26 mutant. It is speculated that subcellular distribution of LKB1 is regulated in the balance of these two forces, importation into the nucleus and retention within the cytoplasm; and the cytoplasmic retention ability is necessary for LKB1 to fulfil its normal function.
    Biochemical and Biophysical Research Communications 09/1999; 261(3):750-5. DOI:10.1006/bbrc.1999.1047 · 2.28 Impact Factor

Publication Stats

3k Citations
149.78 Total Impact Points


  • 2005–2011
    • The University of Tokyo
      • Research Center for Advanced Science and Technology
      Edo, Tōkyō, Japan
  • 2010
    • Waseda University
      • Department of Integrative Bioscience and Biomedical Engineering
      Edo, Tōkyō, Japan
  • 2002
    • KAKEN Pharmaceutical Co.,Ltd
      New York City, New York, United States
  • 1999–2000
    • Japan Research Institute
      Ibaragi, Ōsaka, Japan
    • Clinical Research Hospital, Tokyo
      Edo, Tōkyō, Japan
  • 1998
    • Kanazawa University
      • Graduate School of Natural Science and Technology
      Kanazawa, Ishikawa, Japan