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| 1.
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論文
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Hashizume, Chieko ; Nakano, Hiroshi ; Yoshida, Kimihisa ; Wong, Richard W.
概要:
Nuclear pore complexes are massive multiprotein channels responsible for traffic between the nucleus and cytoplasm, and
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are composed of approximately 30 proteins, termed nucleoporins (Nup). Our recent studies indicated that the nucleoporins Rae1 and Tpr play critical roles in maintaining the spindle bipolarity during cell division. In the present study, we found that another nucleoporin, Nup88, was localized on the spindles together with Nup214 during mitosis. Nup88 expression is linked to the progression of carcinogenesis, Nup88 has been proposed as a tumor marker. Overexpression of Nup88 enhanced multinucleated cell formation. RNAi-mediated knockdown of Nup88 disrupted Nup214 expression and localization and caused multipolar spindle phenotypes. Our data indicate that proper expression of Nup88 is critical for preventing aneuploidy formation and tumorigenesis. © 2010 Hashizume et al; licensee BioMed Central Ltd.
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| 2.
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論文
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Funasaka, Tatsuyoshi ; Nakano, Hiroshi ; Wu, Yu ; Hashizume, Chieko ; Gu, Ling ; Nakamura, Takuro ; Wang, Wei ; Zhou, Pengbo ; Moore, Malcolm AS ; Sato, Hiroshi ; Wong, Richard W.
概要:
金沢大学フロンティアサイエンス機構<br />Chromosomal translocations involving chimeric fusions of the nucleoporin NUP98 protein have often
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been described in acute myelogenous leukemia (AML). All the fusion proteins have an identical NUP98 N terminus, which contains the GLEBS motif for interaction with the mRNA export factor RAE1 and FG repeats that associate with the transcription factors HDAC1 and p300. It is virtually unknown whether these interaction partners affect leukemogenesis. We previously showed that RAE1 depletion caused aneuploidy, which enhanced tumorigenesis. We speculated that RAE1 may also be directly involved in NUP98 fusion-mediated leukemogenesis. We show here that RNA interference (RNAi)-mediated knockdown of NUP98 caused severe chromosome segregation defects and disrupted RAE1 but not HDAC1 expression and localization. Next, we performed rescue experiments to confirm that the RAE1-NUP98 complex orchestrates proper chromosome segregation. Interestingly, we found diverse behaviors of NUP98 and the leukemogenic fusion protein NUP98-HOXA9 throughout the cell cycle. Strikingly, in NUP98-HOXA9-transfected cells, RAE1 protein were reduced and mis-localized. Our cellular interpretations were further confirmed by NUP98-HOXA9 transgenic mice and the NUP98-HOXA9 AML patient. These data suggest that RAE1 orchestrates NUP98-mediated leukemogenesis and raise the possibility that targeting this negative feedback loop may provide a new strategy for the therapy of aggressive leukemias. © 2011 Landes Bioscience.
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| 3.
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論文
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Sakr, Moustafa A. ; Takino, Takahisa ; Domoto, Takahiro ; Nakano, Hiroshi ; Wong, Richard W. ; Sasaki, Motoko ; Nakanuma, Yasuni ; Sato, Hiroshi
概要:
GI24, an immunoglobulin superfamily member, has been cloned from a placenta cDNA library as a gene product that promoted
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activation of matrix metalloproteinase (MMP)-2 mediated by membrane type (MT) 1-MMP. Co-expression of GI24 with MT1-MMP in HEK293T cells increased the cell-surface level of MT1-MMP concomitant with the cleavage of the GI24 at the juxtamembrane site to shed the extracellular domain. HT1080 fibrosarcoma cells stably transfected with the GI24 gene expressed a higher level of MT1-MMP and showed more invasive ability in collagen gel than the control cells. GI24 was cleaved in HT1080 cells, which was blocked by the administration of MMP inhibitor BB94 or transfection of small interfering RNA (siRNA) targeting MT1-MMP. GI24 expression is relatively high in some squamous carcinoma and hepatocarcinoma cell lines. Transfection of siRNA for GI24 into oral squamous carcinoma-derived HSC-4 cells, which express GI24 and MT1-MMP genes reduced the expression of not only GI24 but also MT1-MMP, and attenuated invasive growth in the collagen matrix. These results suggest that GI24 contributes to tumor-invasive growth in the collagen matrix by augmenting cell surface MT1-MMP. (Cancer Sci 2010; 101: 2368-2374) © 2010 Japanese Cancer Association.
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