研究者業績

原口 健

ハラグチ タケシ  (HARAGUCHI TAKESHI)

基本情報

所属
千葉大学 真菌医学研究センター 特任准教授
学位
博士(理学)(2009年3月 東京大学大学院理学系研究科)

J-GLOBAL ID
201801014202869458
researchmap会員ID
B000287561

論文

 21
  • Hiramatsu H, Kobayashi K, Kobayashi K, Haraguchi T, Ino Y, Todo T, Iba H
    Scientific reports 8(1) 16079 2018年10月  査読有り
  • Kobayashi K, Hiramatsu H, Nakamura S, Kobayashi K, Haraguchi T, Iba H
    Scientific reports 7(1) 11772 2017年9月  査読有り
  • Kyousuke Kobayashi, Fumiko Suemasa, Hiroshi Sagara, Shinya Nakamura, Yasushi Ino, Kazuyoshi Kobayashi, Hiroaki Hiramatsu, Takeshi Haraguchi, Kazuo Kurokawa, Tomoki Todo, Akihiko Nakano, Hideo Iba
    SCIENTIFIC REPORTS 7(1) 6650 2017年7月  査読有り
    Because several studies have shown that exogenous miR-199a has antiviral effects against various viruses, including herpesviruses, we examined how miR-199a exerts its antiviral effects using epithelial tumour cell lines infected with herpes simplex virus-1 (HSV-1). We found that both miR-199a-5p and -3p impair the secondary envelopment of HSV-1 by suppressing their common target, ARHGAP21, a Golgi-localized GTPase-activating protein for Cdc42. We further found that the trans-cisternae of the Golgi apparatus are a potential membrane compartment for secondary envelopment. Exogenous expression of either pre-miR-199a or sh-ARHGAP21 exhibited shared phenotypes i.e. alteration of Golgi function in uninfected cells, inhibition of HSV-1 secondary envelopment, and reduction of trans-Golgi proteins upon HSV-1 infection. A constitutively active form of Cdc42 also inhibited HSV-1 secondary envelopment. Endogenous levels of miR-199a in epithelial tumour cell lines were negatively correlated with the efficiency of HSV-1 secondary envelopment within these cells. These results suggest that miR-199a is a crucial regulator of Cdc42 activity on Golgi membranes, which is important for the maintenance of Golgi function and for the secondary envelopment of HSV-1 upon its infection.
  • Hiroaki Hiramatsu, Kazuyoshi Kobayashi, Kyousuke Kobayashi, Takeshi Haraguchi, Yasushi Ino, Tomoki Todo, Hideo Iba
    SCIENTIFIC REPORTS 7(1) 889 2017年4月  査読有り
    Glioma initiating cells (GICs) are thought to contribute to therapeutic resistance and tumor recurrence in glioblastoma, a lethal primary brain tumor in adults. Although the stem-like properties of GICs, such as self-renewal and tumorigenicity, are epigenetically regulated, the role of a major chromatin remodeling complex in human, the SWI/SNF complex, remains unknown in these cells. We here demonstrate that the SWI/SNF core complex, that is associated with a unique corepressor complex through the d4-family proteins, DPF1 or DPF3 alpha, plays essential roles in stemness maintenance in GICs. The serum-induced differentiation of GICs downregulated the endogenous expression of DPF1 and DPF3 alpha, and the shRNA-mediated knockdown of each gene reduced both sphere-forming ability and tumor-forming activity in a mouse xenograft model. Rescue experiments revealed that DPF1 has dominant effects over DPF3 alpha. Notably, whereas we have previously reported that d4-family members can function as adaptor proteins between the SWI/SNF complex and NF-kappa B dimers, this does not significantly contribute to maintaining the stemness properties of GICs. Instead, these proteins were found to link a corepressor complex containing the nuclear receptor, TLX, and LSD1/RCOR2 with the SWI/SNF core complex. Collectively, our results indicate that DPF1 and DPF3a are potential therapeutic targets for glioblastoma.
  • Takeshi Haraguchi, Masayuki Kondo, Ryo Uchikawa, Kazuyoshi Kobayashi, Hiroaki Hiramatsu, Kyousuke Kobayashi, Ung Weng Chit, Takanobu Shimizu, Hideo Iba
    SCIENTIFIC REPORTS 6 21117 2016年2月  査読有り
    Whereas miR-200 family is known to be involved in the epithelial-to-mesenchymal transition (EMT), a crucial biological process observed in normal and pathological contexts, it has been largely unclear how far the functional levels of these tiny RNAs alone can propagate the molecular events to accomplish this process within several days. By developing a potent inhibitor of miR-200 family members (TuD-141/200c), the expression of which is strictly regulatable by the Tet (tetracycline)-On system, we found using a human colorectal cell line, HCT116, that several direct gene target mRNAs (Zeb1/Zeb2, ESRP1, FN1and FHOD1) of miR-200 family were elevated with distinct kinetics. Prompt induction of the transcriptional suppressors, Zeb1/Zeb2 in turn reduced the expression levels of miR-200c/-141 locus, EpCAM, ESRP1 and E-Cad. The loss of ESRP1 subsequently switched the splicing isoforms of CD44 and p120 catenin mRNAs to mesenchymal type. Importantly, within 9 days after the release from the inhibition of miR-200 family, all of the expression changes in the 14 genes observed in this study returned to their original levels in the epithelial cells. This suggests that the inherent epithelial plasticity is supported by a weak retention of key regulatory gene expression in either the epithelial or mesenchymal states through epigenetic regulation.

MISC

 9

講演・口頭発表等

 3

担当経験のある科目(授業)

 1

共同研究・競争的資金等の研究課題

 9

メディア報道

 1