26 results on '"Yoshio Tatematsu"'
Search Results
2. Supplementary Table 2 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Author
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Takashi Takahashi, Yoshitaka Sekido, Yutaka Kondo, Hideki Murakami, Toshiyuki Takeuchi, Yoshio Tatematsu, Yasushi Yatabe, Shuta Tomida, and Hirotaka Osada
- Abstract
Supplementary Table 2 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Published
- 2023
3. Supplementary Methods and Figures 1-2 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Author
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Takashi Takahashi, Yoshitaka Sekido, Yutaka Kondo, Hideki Murakami, Toshiyuki Takeuchi, Yoshio Tatematsu, Yasushi Yatabe, Shuta Tomida, and Hirotaka Osada
- Abstract
Supplementary Methods and Figures 1-2 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Published
- 2023
4. Data from A Polycistronic MicroRNA Cluster, miR-17-92, Is Overexpressed in Human Lung Cancers and Enhances Cell Proliferation
- Author
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Takashi Takahashi, Yoshitaka Sekido, Katsunobu Kawahara, Yasushi Yatabe, Shuta Tomida, Kiyoshi Yanagisawa, Hideki Yamada, Yoshio Tatematsu, Hirotaka Osada, and Yoji Hayashita
- Abstract
MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.
- Published
- 2023
5. Supplementary Figure 1 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Author
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Takashi Takahashi, Yoshitaka Sekido, Yutaka Kondo, Hideki Murakami, Toshiyuki Takeuchi, Yoshio Tatematsu, Yasushi Yatabe, Shuta Tomida, and Hirotaka Osada
- Abstract
Supplementary Figure 1 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Published
- 2023
6. Supplementary Table 3 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Author
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Takashi Takahashi, Yoshitaka Sekido, Yutaka Kondo, Hideki Murakami, Toshiyuki Takeuchi, Yoshio Tatematsu, Yasushi Yatabe, Shuta Tomida, and Hirotaka Osada
- Abstract
Supplementary Table 3 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Published
- 2023
7. Data from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Author
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Takashi Takahashi, Yoshitaka Sekido, Yutaka Kondo, Hideki Murakami, Toshiyuki Takeuchi, Yoshio Tatematsu, Yasushi Yatabe, Shuta Tomida, and Hirotaka Osada
- Abstract
The proneural basic-helix-loop-helix protein achaete-scute homologue 1 (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/β-catenin signaling, E-cadherin, and integrin β1 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions. [Cancer Res 2008;68(6):1647–55]
- Published
- 2023
8. Supplementary Table 1 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Author
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Takashi Takahashi, Yoshitaka Sekido, Yutaka Kondo, Hideki Murakami, Toshiyuki Takeuchi, Yoshio Tatematsu, Yasushi Yatabe, Shuta Tomida, and Hirotaka Osada
- Abstract
Supplementary Table 1 from Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
- Published
- 2023
9. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation
- Author
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Yutaka Kondo, Kaoru Shimokata, Toyoaki Hida, Hirotaka Osada, Yoshinori Hasegawa, Yoshitsugu Horio, Toshihiko Yokoyama, Yoshio Tatematsu, Hideki Murakami, Yoshitaka Sekido, Yasushi Yatabe, and Tetsuo Taniguchi
- Subjects
Mesothelioma ,Chromosomes, Artificial, Bacterial ,Cancer Research ,Tumor suppressor gene ,Ubiquitin-Protein Ligases ,Biology ,Polymerase Chain Reaction ,Inhibitor of Apoptosis Proteins ,Humans ,Phosphorylation ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,DNA Primers ,YAP1 ,Neurofibromin 2 ,Base Sequence ,Oncogene ,Cell growth ,Chromosomes, Human, Pair 11 ,Chromosome Mapping ,YAP-Signaling Proteins ,General Medicine ,Transfection ,Flow Cytometry ,Phosphoproteins ,Merlin (protein) ,Cancer research ,Nucleic Acid Conformation ,RNA Interference ,Signal transduction ,Transcription Factors - Abstract
We previously reported the results of bacterial artificial chromosome array comprehensive genomic hybridization of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional coactivator was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor suppressor gene, which is frequently mutated in MPMs. YAP1-RNA interference suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, whereas YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at serine 127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S 127A mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth and that the transcriptional coactivator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies.
- Published
- 2008
10. CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells
- Author
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Masato Nagino, Yoshio Tatematsu, Takashi Takahashi, H Matsubara, Y Sekido, Hirotaka Osada, Hirotaka Nagai, Toyoaki Hida, Yuji Nimura, and Nobuyoshi Sugito
- Subjects
Proteasome Endopeptidase Complex ,Cancer Research ,Lung Neoplasms ,Phage display ,Leupeptins ,Immunoprecipitation ,Sema domain ,Immunoblotting ,Motility ,Semaphorins ,Cysteine Proteinase Inhibitors ,Biology ,Transfection ,medicine.disease_cause ,Cell Line ,Metastasis ,Semaphorin ,Cell Movement ,Peptide Library ,RNA interference ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Molecular Biology ,Cell Proliferation ,Ubiquitin ,Tunicamycin ,Membrane Proteins ,medicine.disease ,Cancer research ,RNA Interference ,Carcinogenesis ,Oligopeptides ,Proteasome Inhibitors ,Protein Binding - Abstract
We previously established a highly metastatic subline, LNM35, from the NCI-H460 lung cancer cell line, and demonstrated upregulation of a novel gene, CLCP1 (CUB, LCCL-homology, coagulation factor V/VIII homology domains protein), in LNM35 and lung cancer specimens. In this study, we focused on the potential roles of that gene in cancer metastasis. First, we established stable LNM35 RNAi clones, in which CLCP1 expression was suppressed by RNAi, and found that their motility was significantly reduced, although growth rates were not changed. Next, in vitro selection of a phage display library demonstrated that a phage clone displaying a peptide similar to a sequence within the Sema domain of semaphorin 4B (SEMA4B) interacted with LNM35. Immunoprecipitation experiments confirmed interaction of CLCP1 with SEMA4B, regulation of CLCP1 protein by ubiquitination and proteasome degradation enhanced in the presence of SEMA4B. These results are the first to indicate that CLCP1 plays a role in cell motility, whereas they also showed that at least one of its ligands is SEMA4B and that their interaction mediates proteasome degradation by CLCP1. Although the physiological role of the interaction between CLCP1 and SEMA4B remains to be investigated, this novel gene may become a target of therapy to inhibit metastasis of lung cancers.
- Published
- 2007
11. ASH1 Gene Is a Specific Therapeutic Target for Lung Cancers with Neuroendocrine Features
- Author
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Yoshitsugu Horio, Yasushi Yatabe, Takashi Takahashi, Yoshio Tatematsu, and Hirotaka Osada
- Subjects
G2 Phase ,Cancer Research ,Lung Neoplasms ,Cell cycle checkpoint ,Apoptosis ,Cell Growth Processes ,Mice, SCID ,Biology ,Transfection ,medicine.disease_cause ,Mice ,RNA interference ,Cell Line, Tumor ,Basic Helix-Loop-Helix Transcription Factors ,medicine ,Animals ,Humans ,Lung cancer ,Lung ,Cell growth ,Genetic Therapy ,medicine.disease ,Xenograft Model Antitumor Assays ,respiratory tract diseases ,medicine.anatomical_structure ,Oncology ,Cell culture ,Immunology ,Cancer research ,Female ,RNA Interference ,Carcinogenesis ,Cell Division - Abstract
Lung cancers with neuroendocrine features are usually aggressive, although the underlying molecular mechanisms largely remain to be determined. The basic helix-loop-helix protein, achaete-scute complex-like 1/achaete-scute homologue 1 (ASH1), is expressed in normal fetal pulmonary neuroendocrine cells and lung cancers with neuroendocrine elements and is suggested to be involved in lung carcinogenesis. In the present study, we show inhibition of ASH1 expression by plasmid-based RNA interference (RNAi) to significantly suppress growth of lung cancer cells with ASH1 expression through G2-M cell cycle arrest and accumulation of sub-G1 populations, possibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASH1 expression and immortalized normal BEAS2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASH1 clearly induced rescue from G2-M arrest, suggesting a target-specific effect of RNAi. An ASH1-RNAi adenovirus was also established and significantly inhibited not only in vitro cell proliferation but also in vivo xenograft growth of ASH1-positive NCI-H460 cells. Elevated levels of apoptosis were also observed in NCI-H460 xenografts with the ASH1-RNAi adenovirus. The present study therefore suggests that ASH1 plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with neuroendocrine features.
- Published
- 2005
12. A Polycistronic MicroRNA Cluster, miR-17-92, Is Overexpressed in Human Lung Cancers and Enhances Cell Proliferation
- Author
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Takashi Takahashi, Hirotaka Osada, Katsunobu Kawahara, Hideki Yamada, Yoshitaka Sekido, Yoji Hayashita, Yasushi Yatabe, Yoshio Tatematsu, Kiyoshi Yanagisawa, and Shuta Tomida
- Subjects
Cancer Research ,Lung Neoplasms ,Molecular Sequence Data ,Gene Dosage ,Gene Expression ,Cell Growth Processes ,Biology ,Open Reading Frames ,Gene duplication ,microRNA ,medicine ,Humans ,Carcinoma, Small Cell ,Lung cancer ,Gene ,Expression vector ,Base Sequence ,Cell growth ,Gene Amplification ,Intron ,medicine.disease ,MicroRNAs ,Open reading frame ,Oncology ,Multigene Family ,Immunology ,Cancer research - Abstract
MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.
- Published
- 2005
13. Reduced expression of Dicer associated with poor prognosis in lung cancer patients
- Author
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Shinichiro Miyoshi, Takahashi Takahashi, Kiyoshi Yanagisawa, Yoko Karube, Yoshio Tatematsu, Tetsuya Mitsudomi, Hirotaka Osada, Yasushi Yatabe, Shuta Tomida, Hisaaki Tanaka, and Junichi Takamizawa
- Subjects
Adult ,Male ,Ribonuclease III ,Cancer Research ,Lung Neoplasms ,XPO5 ,Pathogenesis ,Carcinoma, Non-Small-Cell Lung ,microRNA ,medicine ,Humans ,Lung cancer ,Survival analysis ,Drosha ,Aged ,biology ,Smoking ,Cancer ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,MicroRNAs ,Oncology ,Immunology ,biology.protein ,Cancer research ,Female ,Dicer - Abstract
Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P=0.001) appears to be independent of disease stage (P=0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P=0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.
- Published
- 2005
14. Persistent Increase in Chromosome Instability in Lung Cancer
- Author
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Akira Masuda, Hirotaka Osada, Tomoko Harano, Yoshio Tatematsu, Hiroyuki Konishi, Takao Takahashi, Nobuhiro Haruki, Shigeki Shimizu, Yoshitaka Fujii, Tetsuya Mitsudomi, Tohru Kiyono, and Takashi Takahashi
- Subjects
Mutation ,medicine.diagnostic_test ,Aneuploidy ,Karyotype ,Biology ,medicine.disease ,medicine.disease_cause ,female genital diseases and pregnancy complications ,Pathology and Forensic Medicine ,Spindle apparatus ,Chromosome instability ,medicine ,Cancer research ,Lung cancer ,Mitosis ,Fluorescence in situ hybridization - Abstract
Karyotype and fluorescence in situ hybridization analyses have demonstrated the frequent presence of an altered static state of the number of chromosomes (ie, aneuploidy) in lung cancer, but it has not been directly established whether aneuploidy is in fact associated with a persistent increase in the rate of chromosomal losses and gains (ie, chromosome instability, or CIN). The study presented here used a panel of 10 lung cancer cell lines to provide for the first time direct evidence that CIN is a common feature in lung cancer cell lines in association with the presence of significant aneuploidy. In addition, we found that the CIN phenotype correlates well with the presence of p53 mutations. However, human papilloma virus 16-E6-directed inactivation of p53 in a representative non-CIN lung cancer cell line did not result in the induction of CIN, at least up to the 25th generation, suggesting that inactivation of p53 itself is unlikely to directly induce CIN in lung cancer cells. Interestingly, however, significant CIN could be induced in conjunction with the generation of aneuploid populations when the mitotic spindle formation was transiently abrogated in p53-inactivated cells. These results suggest that inactivation of p53 may allow lung cancer cells to go through an inappropriate second division cycle under certain forms of mitotic stresses, which would result in the induction of the CIN phenotype in conjunction with the generation of aneuploidy.
- Published
- 2001
15. Multi-faceted analyses of a highly metastatic human lung cancer cell line NCI-H460-LNM35 suggest mimicry of inflammatory cells in metastasis
- Author
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Osamu Miyaishi, Ken Ichi Kozaki, Takashi Takahashi, Katsumi Koshikawa, Yoshio Tatematsu, Hiroko Saito, Hirotaka Osada, and Toyoaki Hida
- Subjects
Cancer Research ,Chemokine ,Lung Neoplasms ,Mice, Nude ,Inflammation ,Mice, SCID ,Metastasis ,Proinflammatory cytokine ,Mice ,In vivo ,Tumor Cells, Cultured ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Lung cancer ,Molecular Biology ,Oligonucleotide Array Sequence Analysis ,biology ,Gene Expression Profiling ,Membrane Proteins ,Chemotaxis ,medicine.disease ,Isoenzymes ,Phenotype ,Cyclooxygenase 2 ,Prostaglandin-Endoperoxide Synthases ,Cell culture ,Immunology ,biology.protein ,Cancer research ,Female ,medicine.symptom - Abstract
This study established and characterized low-metastatic revertant and parental clones of a highly metastatic human lung cancer cell line, NCI-H460-LNM35 (hereafter referred to as LNM35). Expression-profiling analysis revealed that up-regulation of various proinflammatory cytokines and angiogenic chemotactic chemokines was present in LNM35. Further, while COX-2 itself is known to be inducible in inflammation, COX-2 expression levels correlated well with the capabilities of these clones for not only in vitro motility and invasion but also in vivo metastasis, and COX-2 inhibitors were shown for the first time to reduce lung cancer metastasis in vivo. These findings suggest that lung cancer cells may mimic inflammatory cells in the process of metastasis.
- Published
- 2001
16. Protective Function of p27KIP1 against Apoptosis in Small Cell Lung Cancer Cells in Unfavorable Microenvironments
- Author
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Ken Ichi Kozaki, Yoshio Tatematsu, Akira Masuda, Takao Takahashi, Toyoaki Hida, Toshitada Takahashi, Yasushi Yatabe, Hirotaka Osada, and Takashi Takahashi
- Subjects
Lung Neoplasms ,Blotting, Western ,Cell ,Oligonucleotides ,Apoptosis ,Cell Cycle Proteins ,Mice, SCID ,medicine.disease_cause ,Resting Phase, Cell Cycle ,DNA, Antisense ,S Phase ,Pathology and Forensic Medicine ,Mice ,Cyclin-dependent kinase ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Carcinoma, Small Cell ,Isoleucine ,neoplasms ,Dose-Response Relationship, Drug ,biology ,Cell growth ,Tumor Suppressor Proteins ,G1 Phase ,Cell cycle ,Culture Media ,medicine.anatomical_structure ,Gene Expression Regulation ,Cell culture ,Immunology ,biology.protein ,Cancer research ,Female ,biological phenomena, cell phenomena, and immunity ,Carcinogenesis ,Microtubule-Associated Proteins ,Cell Division ,Cyclin-Dependent Kinase Inhibitor p27 ,CDK inhibitor ,Regular Articles - Abstract
A previous study of ours unexpectedly found that in contrast to frequent reductions in non-small cell lung cancer, high expression of the p27 KIP1 cyclin-dependent kinase (CDK) inhibitor was retained in virtually all small cell lung cancers (SCLCs), suggesting the possibility of high expression of nonfunctional p27 KIP1 in this virulent tumor. The study presented here, however, shows that p27 KIP1 in SCLC biochemically functions as a CDK inhibitor, clearly showing induction apparently associated with G 1 /G 0 arrest and efficient binding to and inhibition of the cyclin E-CDK2 complex. Interestingly, induction of p27 KIP1 seems to confer on SCLC cells the ability to survive under culture conditions unfavorable for cell growth such as a lack of nutrients and hypoxia. Subsequent experiments manipulating p27 KIP1 levels by using a sense p27 KIP1 expression construct or an antisense oligonucleotide supported this notion. These observations suggest that high expression of p27 KIP1 in vivo may favor the survival of SCLC by preventing apoptosis in a microenvironment unfavorable for cell proliferation.
- Published
- 2001
17. miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer
- Author
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Yoshio Tatematsu, Chinatsu Arima, Yoshitaka Sekido, Ayumu Taguchi, Kiyoshi Yanagisawa, Shuta Tomida, Shinya Toyokuni, Yasumasa Okazaki, Yukako Shimada, Takashi Takahashi, Eri Nishikawa, Yasushi Yatabe, and Hirotaka Osada
- Subjects
Cancer Research ,Lung Neoplasms ,Cellular differentiation ,Adenocarcinoma of Lung ,Biology ,Adenocarcinoma ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Carcinoma, Small Cell ,Lung cancer ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,YAP1 ,Effector ,Cell growth ,Cell Differentiation ,YAP-Signaling Proteins ,respiratory system ,medicine.disease ,Phosphoproteins ,Gene Expression Regulation, Neoplastic ,ASCL1 ,MicroRNAs ,Oncology ,Cancer cell ,Cancer research ,Transcription Factors - Abstract
Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. Cancer Res; 71(19); 6165–73. ©2011 AACR.
- Published
- 2011
18. Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer
- Author
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Toshiyuki Takeuchi, Yasushi Yatabe, Takashi Takahashi, Shuta Tomida, Hideki Murakami, Yutaka Kondo, Hirotaka Osada, Yoshitaka Sekido, and Yoshio Tatematsu
- Subjects
Cancer Research ,Lung Neoplasms ,Cellular differentiation ,Down-Regulation ,Biology ,Adenocarcinoma ,medicine.disease_cause ,Neuroendocrine differentiation ,Cell Line, Tumor ,medicine ,Humans ,Gene Silencing ,Carcinoma, Small Cell ,Promoter Regions, Genetic ,Transcription factor ,Adaptor Proteins, Signal Transducing ,Cadherin ,Gene Expression Profiling ,Integrin beta1 ,Wnt signaling pathway ,Cell Differentiation ,Histone-Lysine N-Methyltransferase ,DNA Methylation ,medicine.disease ,Cadherins ,Carcinoma, Neuroendocrine ,DNA-Binding Proteins ,Oncology ,Immunology ,DNA methylation ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Chemokines ,Carcinogenesis ,Transcription Factors - Abstract
The proneural basic-helix-loop-helix protein achaete-scute homologue 1 (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/β-catenin signaling, E-cadherin, and integrin β1 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions. [Cancer Res 2008;68(6):1647–55]
- Published
- 2008
19. Significant growth inhibition of human lung cancer cells both in vitro and in vivo by the combined use of a selective cyclooxygenase 2 inhibitor, JTE-522, and conventional anticancer agents
- Author
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Toyoaki, Hida, Ken-Ichi, Kozaki, Hidemi, Ito, Osamu, Miyaishi, Yoshio, Tatematsu, Takeshi, Suzuki, Keitaro, Matsuo, Takahiko, Sugiura, Makoto, Ogawa, Toshitada, Takahashi, and Takashi, Takahashi
- Subjects
Lung Neoplasms ,Paclitaxel ,Mice, Nude ,Docetaxel ,Adenocarcinoma ,In Vitro Techniques ,Vinblastine ,Mice ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Animals ,Humans ,Anthracyclines ,Cyclooxygenase Inhibitors ,Oxazoles ,Antibiotics, Antineoplastic ,Cyclooxygenase 2 Inhibitors ,Benzenesulfonates ,Membrane Proteins ,Vinorelbine ,Isoenzymes ,Cyclooxygenase 2 ,Drug Resistance, Neoplasm ,Prostaglandin-Endoperoxide Synthases ,Female ,Taxoids ,Cell Division ,Neoplasm Transplantation - Abstract
This study reports that a selective COX-2 inhibitor JTE-522inhibits both in vitro and in vivo growth of human lung cancer cells as a single agent. Furthermore, the adjunct use of JTE-522 is shown to significantly enhance treatment efficacy of conventional anticancer drugs not only in vitro but also in vivo without causing any noticeable side effects. Indeed, IC(50)s of various anticancer agents in vitro were reduced by up to 70%, whereas the combination therapy of JTE-522 with docetaxel and vinorelbine inhibited tumor growth in vivo by 65 and 55%, respectively. Taken together, these findings suggest that the use of a selective COX-2 inhibitor in the treatment of lung cancer may be promising, especially because of its enhancement of the treatment efficacy of conventional anticancer agents without compromising quality of life.
- Published
- 2002
20. Decreased expression of 14-3-3sigma in neuroendocrine tumors is independent of origin and malignant potential
- Author
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Hirotaka Osada, Takashi Takahashi, Yasushi Yatabe, Tetsuya Mitsudomi, and Yoshio Tatematsu
- Subjects
Exonucleases ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Cell ,Biology ,Neuroendocrine tumors ,Internal medicine ,Genetics ,medicine ,Biomarkers, Tumor ,Gene silencing ,Humans ,Molecular Biology ,DNA Primers ,Base Sequence ,Cell growth ,Large cell ,DNA Methylation ,medicine.disease ,Immunohistochemistry ,Neoplasm Proteins ,Neuroendocrine Tumors ,Endocrinology ,medicine.anatomical_structure ,14-3-3 Proteins ,DNA methylation ,Exoribonucleases ,Cancer research ,Stem cell - Abstract
We recently reported that 14-3-3sigma is frequently inactivated in small cell lung cancer (SCLC) and a part of large cell carcinomas. Subsequent studies revealed that the large cell carcinomas could be morphologically categorized as large cell neuroendocrine carcinomas (LCNEC). The present study therefore examines 14-3-3sigma expression in a spectrum of neuroendocrine lung tumors, which had varied p53 status, proliferative activity and clinical aggressiveness. The expression of 14-3-3sigma was decreased in all four categories of the spectrum, (5 out of 5 typical carcinoids, 2 out of 2 atypical carcinoids, 5 out of 7 LCNECs and 15 out of 18 SCLCs). In sharp contrast, the level of 14-3-3sigma expression in 75 non-small cell lung cancers (NSCLCs) was the same as that in normal lung tissue, with only one exception. The expression status of neuroendocrine tumors and NSCLCs was not affected by p53 status, but dense promoter hypermethylation of the 14-3-3sigma gene was specifically observed in neuroendocrine tumors, suggesting that methylation plays a regulatory role in 14-3-3sigma expression in vivo as well as in vitro. Furthermore, the expression was not only down-regulated in pulmonary neuroendocrine tumors, but also in neuroendocrine tumors arising from various other organs, through examination of 123 non-pulmonary tumors. Since various carcinogenic machineries are involved in the neuroendocrine tumors, a reduced expression of 14-3-3sigma might be required for the development of neuroendocrine tumors. Constitutive 14-3-3sigma expression was distributed exclusively in putative stem cells of the normal lung, namely the basal cells of the bronchus, and type II pneumocytes. Notably, 14-3-3sigma expression was up-regulated during the regeneration of type II pneumocytes, suggesting that 14-3-3sigma plays a biological role when a regenerative and/or differentiating drive is activated, facilitating exit from stem cells.
- Published
- 2002
21. Significant up-regulation of a novel gene, CLCP1, in a highly metastatic lung cancer subline as well as in lung cancers in vivo
- Author
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Hiroyuki Konishi, Akimasa Nakao, Katsumi Koshikawa, Yoshio Tatematsu, Ken Ichi Kozaki, Akira Masuda, Tetsuya Mitsudomi, Hirotaka Osada, and Takashi Takahashi
- Subjects
Adult ,Cancer Research ,DNA, Complementary ,Lung Neoplasms ,Neuropilins ,Molecular Sequence Data ,Biology ,Adenocarcinoma ,Chemical Fractionation ,Transfection ,Metastasis ,Semaphorin ,Cell surface receptor ,In vivo ,Sequence Homology, Nucleic Acid ,Genetics ,medicine ,Tumor Cells, Cultured ,Humans ,Amino Acid Sequence ,Carcinoma, Small Cell ,Cloning, Molecular ,Neoplasm Metastasis ,Lung cancer ,Molecular Biology ,Gene ,Base Sequence ,Membrane Proteins ,medicine.disease ,Neoplasm Proteins ,Up-Regulation ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,Immunology ,Cancer research ,Carcinoma, Squamous Cell ,Carcinoma, Large Cell - Abstract
Most lung cancer patients are unfortunately uncurable and die because of widespread metastases, thus indicating the importance of identification of molecules with a crucial role in this process. Our previous expression profiling analysis of a highly metastatic lung cancer cell line, NCI-H460-LNM35, and its parental low metastatic line, NCI-H460-N15, revealed significant up-regulation of both known and unknown genes in LNM35. In this study, we describe the isolation and detailed characterizations of a novel gene, named CLCP1, which corresponds to one of such expression sequence tags with up-regulated expression in LNM35. The CLCP1 gene was found to encode a protein with 775 amino acids with structural similarities to, but distinct from neuropilins, cell surface receptors for VEGF165 and semaphorins. Notably, CLCP1 was shown to be up-regulated not only in LNM35 in association with its acquisition of metastatic phenotype during in vivo selection, but also in a significant fraction of lung cancers in vivo with high frequency in metastatic lesions, warranting future studies for a better understanding of the molecular mechanisms of lung cancer metastasis.
- Published
- 2001
22. Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers
- Author
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Yasushi Yatabe, Hiroyuki Konishi, Yoshitaka Fujii, Kotaro Mizuno, Hirotaka Osada, Tetsuya Mitsudomi, Yoshio Tatematsu, and Takashi Takahashi
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Cancer Research ,Lung Neoplasms ,Ubiquitin-Protein Ligases ,Mitotic prophase ,Cell Cycle Proteins ,Biology ,medicine.disease_cause ,Prophase ,chemistry.chemical_compound ,CHFR ,Genetics ,medicine ,Tumor Cells, Cultured ,Humans ,Gene Silencing ,RNA, Neoplasm ,Lung cancer ,Poly-ADP-Ribose Binding Proteins ,Promoter Regions, Genetic ,Molecular Biology ,Mitosis ,Polymorphism, Genetic ,Base Sequence ,DNA, Neoplasm ,Cell cycle ,DNA Methylation ,medicine.disease ,Demethylating agent ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,chemistry ,DNA methylation ,Cancer research ,Carcinogenesis - Abstract
The CHFR gene, which was recently cloned by Scolnick and Halazonetis in search for a novel mitotic checkpoint gene with fork-head association motifs, has been suggested to play a key role in the mitotic prophase checkpoint. In this study, we demonstrated tumor-specific aberrant hypermethylation of the promoter region of the CHFR gene in a significant fraction of lung cancers in association with loss of detectable levels of CHFR transcripts. Aberrant hypermethylation was observed in seven of 37 primary lung cancer cases. Treatment with the demethylating agent 5-aza-2'-deoxycytidine restored expression of the CHFR gene in lung cancer cell lines exhibiting aberrant hypermethylation and loss of its expression. In contrast, genetic alterations were found to be infrequent in lung cancers. This is the first description of aberrant hypermethylation of the CHFR gene in any type of human cancer, and provides further evidence of the involvement of multiple checkpoint alterations in lung cancer.
- Published
- 2001
23. Frequent and histological type-specific inactivation of 14-3-3sigma in human lung cancers
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Minoru Takada, Tomoko Harano, Taku Nakagawa, Takashi Takahashi, Yoshio Tatematsu, Hiroyuki Konishi, Yasushi Yatabe, Ekmel Tezel, and Hirotaka Osada
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Exonucleases ,Cancer Research ,Lung Neoplasms ,Cell ,Biology ,medicine.disease_cause ,Carcinoma, Non-Small-Cell Lung ,Genetics ,medicine ,Carcinoma ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Gene silencing ,Humans ,Gene Silencing ,RNA, Neoplasm ,Carcinoma, Small Cell ,Lung cancer ,Molecular Biology ,Regulation of gene expression ,Proteins ,DNA, Neoplasm ,G2-M DNA damage checkpoint ,DNA Methylation ,medicine.disease ,respiratory tract diseases ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,14-3-3 Proteins ,Protein Biosynthesis ,Immunology ,DNA methylation ,Exoribonucleases ,Cancer research ,Carcinogenesis - Abstract
One isoform of the 14-3-3 family, 14-3-3sigma, plays a crucial role in the G2 checkpoint by sequestering Cdc2-cyclinB1 in the cytoplasm, and the expression of 14-3-3sigma is frequently lost in breast cancers. This loss of expression is thought to cause a G2 checkpoint defect, resulting in chromosomal aberrations. Since lung cancers frequently carry numerous chromosomal aberrations, we examined the DNA methylation status and expression level of the 14-3-3sigma gene in 37 lung cancer cell lines and 30 primary lung tumor specimens. We found that small cell lung cancer (SCLC) cell lines frequently showed DNA hypermethylation (9 of 13 lines, 69%), and subsequent silencing of the 14-3-3sigma gene. Among non-small cell lung cancers (NSCLC), large cell lung cancer cell lines showed frequent hypermethylation and silencing of 14-3-3sigma (4 or 7 lines, 57%). In contrast, in other NSCLC cell lines, hypermethylation occurred very rarely (1 of 17 lines, 6%). All eight primary SCLC specimens examined also showed a loss or significant reduction in 14-3-3sigma expression in vivo, while a loss or reduction of 14-3-3sigma expression was very rare in primary NSCLC specimens (1 of 22 tissues, 5%). This is the first description that indicates lung cancers frequently show significant inactivation of the 14-3-3sigma gene mainly due to DNA hypermethylation in SCLC, but rarely in NSCLC, suggesting involvement of the 14-3-3sigma gene in lung tumorigenesis in a histological type-specific manner.
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- 2001
24. Cloning and characterization of the alternative promoter regions of the human LIMK2 gene responsible for alternative transcripts with tissue-specific expression
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Shuji Nomoto, Hirotaka Osada, Yoshio Tatematsu, and Takashi Takahashi
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Gene isoform ,Transcriptional Activation ,Transcription, Genetic ,Placenta ,Molecular Sequence Data ,Kruppel-Like Transcription Factors ,Receptors, Cytoplasmic and Nuclear ,Biology ,Protein Serine-Threonine Kinases ,Regulatory Sequences, Nucleic Acid ,Genes, Reporter ,Genetics ,Transcriptional regulation ,Tumor Cells, Cultured ,Humans ,Protein Isoforms ,Tissue Distribution ,Cloning, Molecular ,Promoter Regions, Genetic ,Gene ,Gene Library ,Regulation of gene expression ,Reporter gene ,Base Sequence ,Models, Genetic ,Reverse Transcriptase Polymerase Chain Reaction ,Alternative splicing ,Lim Kinases ,Promoter ,Nuclear Receptor Subfamily 1, Group F, Member 1 ,General Medicine ,Molecular biology ,DNA-Binding Proteins ,Alternative Splicing ,Gene Expression Regulation ,Regulatory sequence ,Organ Specificity ,Trans-Activators ,Transcription Factors - Abstract
We previously isolated the human LIMK2 gene and identified two alternative transcripts, LIMK2a and LIMK2b, which were differentially regulated in a tissue-specific manner. To examine this differential tissue-specific expression in detail, an RNase protection assay was performed, which demonstrated three expression patterns of the LIMK2 isoforms. In digestive organs, the LIMK2a transcripts were preferentially expressed in fetal and adult tissues; in brain and lung, the LIMK2a transcript was predominantly expressed only in fetal tissue, and in placenta, the LIMK2b transcript was expressed more abundantly than that of LIMK2a. To further investigate this mechanism and the transcription factors involved, we isolated the two distinct 5' upstream regions from the phage genomic library and found that both LIMK2a and 2b promoters have a single major transcription initiation site and the characteristics of a TATA-less promoter. A luciferase reporter assay of the transcriptional activity revealed positive as well as negative regulatory regions within both promoters. The co-transfection assay suggested that the MZF-1 might regulate the expression of the LIMK2 isoforms in a different manner. The RORalpha1 might also be involved in the transcriptional regulation of the LIMK2b isoform. The genomic structure of the LIMK2 gene was also determined. These findings should lead to a better understanding of the possibly diverse functions of the LIMK family.
- Published
- 1999
25. Abstract 3992: Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features
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Chinatsu Arima, Yoshitaka Sekido, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Shinya Toyokuni, Osada Hirotaka, Takashi Takahashi, Yukako Shimada, Eri Nishikawa, Yasumasa Okazaki, and Kiyoshi Yanagisawa
- Subjects
A549 cell ,YAP1 ,Cancer Research ,Pathology ,medicine.medical_specialty ,Cell ,Cancer ,Biology ,medicine.disease ,ASCL1 ,medicine.anatomical_structure ,Oncology ,Mir-375 ,microRNA ,medicine ,Cancer research ,Lung cancer - Abstract
Lung cancers with neuroendocrine (NE) features are often very aggressive, though the underlying molecular mechanisms have not been clearly elucidated. We previously reported that the basic helix-loop-helix protein, achaete-scute homologue 1 (ASH1/ASCL1), a master regulator of pulmonary neuroendocrine cell development, is crucially involved in the pathogenesis of lung cancers with neuroendocrine features (NE-lung cancers). In the present study, we searched for miRNAs regulated by ASH1 in order to gain insight into the involvement of miRNAs downstream of ASH1 in NE-lung cancer pathogenesis. We consequently found that introduction of ASH1 into A549 cells markedly induced miR-375 and down-regulated miR-200b. Interestingly, these two miRNAs inversely affected cell-cell interaction and cell motility, and they together conferred looser cell attachment and a more motile feature. miR-375 was found to be directly transactivated by ASH1. Global gene expression analysis using miR-375-introduced A549 cells and the subsequent pathway analysis using the Ingenuity IPA software revealed altered gene expressions in several cancer-related pathways (e.g., cellular movement and morphology). Interestingly, we also found that miR-375 alone can induce NE differentiation markers in A549 cells and that miR-375 is required to elicit ASH1-indued NE features. In accordance with these findings in vitro, clear induction of NE features as well as enhanced tumor growth was observed in xenografts of A549 cells stably expressing miR-375. We further found that a transcriptional co-activator YAP1 is most significantly repressed by miR-375 through recognition of its two miR-375 binding sites. A positive correlation between ASH1 and miR-375 as well as a negative correlation between miR-375 and YAP1 were observed in lung cancers, indicating the ASH1-miR-375-YAP1 regulatory pathway is indeed functionally implemented in lung cancer cells. In addition, we found that growth-regulatory functions of YAP1 is cell-lineage dependent in lung cancer cell lines. In conclusion, the present study identified the ASH1-miR-375 axis, providing clues for a better understanding of the molecular and cellular biological roles of ASH1-centered microRNA regulatory networks in the pathogenesis of NE-lung cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3992. doi:10.1158/1538-7445.AM2011-3992
- Published
- 2011
26. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation.
- Author
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Toshihiko Yokoyama, Hirotaka Osada, Hideki Murakami, Yoshio Tatematsu, Tetsuo Taniguchi, Yutaka Kondo, Yasushi Yatabe, Yoshinori Hasegawa, Kaoru Shimokata, Yoshitsugu Horio, Toyoaki Hida, and Yoshitaka Sekido
- Subjects
MESOTHELIOMA ,GENETIC regulation ,TUMOR suppressor proteins ,PHOSPHORYLATION ,BACTERIAL artificial chromosomes ,GENE amplification ,GENE expression ,ONCOGENES ,CELL lines - Abstract
We previously reported the results of bacterial artificial chromosome array comprehensive genomic hybridization of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional coactivator was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor suppressor gene, which is frequently mutated in MPMs. YAP1-RNA interference suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, whereas YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at serine 127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S 127A mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth and that the transcriptional coactivator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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