RAN cycle and cellular senescence

2011 Fiscal Year Final Research Report

• Project/Area Number: 23657130
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cell biology
• Research Institution: Osaka University
• Principal Investigator: YONEDA Yoshihiro 大阪大学, 生命機能研究科, 教授 (80191667)
• Project Period (FY): 2011
• Keywords: 核輸送 / 細胞老化 / Ran / importin / RanBP1

Research Abstract

The small GTPase Ran, Ras-related nuclear protein, plays important roles in multiple fundamental cellular functions such as nucleocytoplasmic transport, mitotic spindle assembly, and nuclear envelope formation, by binding to either GTP or GDP as a molecular switch. During the long-term culture of normal mammalian cells, I found that the endogenous Ran level gradually reduced in a passage-dependent manner. To examine the physiological significance of Ran reduction, I first performed small interfering RNA(siRNA)-mediated abrogation of Ran in human diploid fibroblasts. Ran-depleted cells showed several senescent phenotypes. Furthermore, I found that nuclear accumulation of importinα, which was also observed in cells treated with siRNA against CAS, a specific export factor for importinα, occurred in the Ran-depleted cells before the cells showed senescent phenotypes. Further, the CAS-depleted cells also exhibited cellular senescence. Indeed, importinα gradually accumulated in a passage-dependent manner. Thus, reduction in Ran levels causes nuclear accumulation of importinα, leading to cellular senescence in normal cells. The amount of intracellular Ran may be critically related to cell senescence. The cellular aging process may proceed through gradual regression of Ran-dependent nucleocytoplasmic transport competency.

Research Products

• [Journal Article] The interaction between importin-alpha and Nup153 promotes importin-alpha/ beta-mediated nuclear import (2012)
  • Author(s): Ogawa, Y., Miyamoto, Y., Oka, M. and Yoneda, Y.
  • Journal Title: Traffic Volume: (in press)
  • Peer Reviewed
• [Journal Article] Intrinsic and extrinsic negative regulators of nuclear protein transport processes (2012)
  • Author(s): Sekimoto, T. and Yoneda, Y.
  • Journal Title: Genes Cells Volume: (in press)
  • Peer Reviewed
• [Journal Article] The small GTPase Ran and Ran-binding proteins (2012)
  • Author(s): Nagai, M. and Yoneda, Y.
  • Journal Title: BioMol. Concepts Volume: (in press)
  • Peer Reviewed
• [Journal Article] Nuclear importinτand its physiological importance (2012)
  • Author(s): Miyamoto, Y., Loveland, K. L. and Yoneda, Y.
  • Journal Title: Commun. Integ. Biol Volume: 5 Pages: 220-222
  • URL: http://dx.doi.org/10.1038/emboj.2011.360
  • Peer Reviewed
• [Journal Article] The role of Rae1 in Nup98-fusion mediated leukemogenesis (2011)
  • Author(s): Oka, M. and Yoneda, Y.
  • Journal Title: Cell Cycle Volume: 10 Pages: 12
  • URL: http://dx.doi.org/10.4161/cc.10.12.15759
  • Peer Reviewed
• [Journal Article] Nucleo-cytoplasmic transport of microRNAs and related small RNAs (2011)
  • Author(s): Katahira, J. and Yoneda, Y.
  • Journal Title: Traffic Volume: 12 Pages: 1468-1474
  • DOI: doi:10.1111/j.1600-0854.2011.01211.x.
  • Peer Reviewed
• [Journal Article] Nuclear retention of importinτcoordinates cell fate through changes in gene expression (2011)
  • Author(s): Yasuda, Y., Miyamoto, Y., Yamashiro, T., Asally, M., Masui, A., Loveland, K. L. and Yoneda, Y.
  • Journal Title: EMBO J Volume: 31 Pages: 83-94
  • DOI: doi:10.1038/emboj.2011.360
  • Peer Reviewed
• [Journal Article] Cell type-dependent gene regulation by Staufen2 in conjunction with Upf1 (2011)
  • Author(s): Miki, T., Kurono, S., Kaneko, Y., Katahira, J. and Yoneda, Y.
  • Journal Title: BMC Mol. Biol Volume: 12 Pages: 48
  • DOI: doi:10.1186/1471-2199-12-48
  • Peer Reviewed
• [Journal Article] Stimulation of CK2-dependent Grp94 phosphorylation by the nuclear localization signal peptide (2011)
  • Author(s): Miyata, Y., Yoneda, Y. and Yahara, I.
  • Journal Title: Mol. Cell. Biochem Volume: 356 Pages: 191-200
  • DOI: DOI:10.1007/s11010-011-0944-9
  • Peer Reviewed
• [Journal Article] Cell type-specific transcriptional regulation of the gene encoding importin-α1 (2011)
  • Author(s): Kamikawa, Y., Yasuhara, N. and Yoneda, Y.
  • Journal Title: Exp. Cell Res Volume: 317 Pages: 1970-1978
  • URL: http://dx.doi.org/10.1016/j.yexcr.2011.05.024
  • Peer Reviewed
• [Journal Article] Targeted disruption of one of the importinα family members leads to female functional incompetence in delivery (2011)
  • Author(s): Moriyama, T., Nagai, M., Oka, M., Ikawa, M., Okabe, M. and Yoneda, Y.
  • Journal Title: FEBS J Volume: 278 Pages: 1561-1572
  • Peer Reviewed
• [Journal Article] Generation and characterization of a monoclonal antibody against importinα7/ NPI-2 (2011)
  • Author(s): Mizuguchi, C., Moriyama, T. and Yoneda, Y.
  • Journal Title: Hybridoma Volume: 30 Pages: 307-309
  • DOI: doi:10.1089/hyb.2011.0006
  • Peer Reviewed
• [Journal Article] Generation of rat monoclonal antibody specific for mouse importinα8 (2011)
  • Author(s): Moriyama, T., Mizuguchi, C. and Yoneda, Y.
  • Journal Title: Hybridoma Volume: 30 Pages: 303-306
  • DOI: doi:10.1089/hyb.2011.0004
  • Peer Reviewed
• [Journal Article] Nuclear import of serum response factor in airway smooth mascle (2011)
  • Author(s): McConville, J. F., Fernandes, D. J., Churchill, J., Dewundara, S., Kogut, P., Shah, S., Fuchs, G., Kedainis, D., Bellam, S. K., Patel, N. M., McCauley, J., Dulin, N. O., Gupta, M. P., Adam, S., Yoneda, Y., Camoretti-Mercado, B. and Solway, J.
  • Journal Title: Am J. Respir. Cell Mol. Biol Volume: 45 Pages: 453-458
  • DOI: doi:10.1165/rcmb.2008-0393OC
  • Peer Reviewed
• [Journal Article] Importinτprotein acts as a negative regulator for Snail protein nuclear import (2011)
  • Author(s): Sekimoto, T., Miyamoto, Y., Arai, S. and Yoneda, Y.
  • Journal Title: J. Biol. Chem Volume: 286 Pages: 15126-15131
  • DOI: doi:10.1074/jbc.M110.213579
  • Peer Reviewed
• [Journal Article] Proteomic analysis of importinα-interacting proteins in adult mouse brain (2011)
  • Author(s): Fukumoto, M., Sekimoto, T. and Yoneda, Y.
  • Journal Title: Cell Struct. Funct Volume: 36 Pages: 57-67
  • DOI: doi:10.1247/csf.10026
  • Peer Reviewed
• [Journal Article] Mice lacking Ran Binding Protein 1 are viable and show male infertility (2011)
  • Author(s): Nagai, M., Moriyama, T., Mehmood, R., Tokuhiro, K., Ikawa, M., Okabe, M., Tanaka, H. and Yoneda, Y.
  • Journal Title: FEBS Lett Volume: 585 Pages: 791-796
  • URL: http://dx.doi.org/10.1016/j.febslet.2011.02.002
  • Peer Reviewed
• [Journal Article] Axotomy induces axonogenesis in hippocampal neurons by a mechanism dependent on importinβ (2011)
  • Author(s): Ohara, R., Hata, K., Yasuhara, N., Mehmood, R., Yoneda, Y., Nakagawa, M. and Yamashita, T.
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 405 Pages: 697-702
  • DOI: 10.1016/j.bbrc.2011.01.108
  • Peer Reviewed
• [Journal Article] NUP358, a nucleoporin, functions as a key determinant of the nuclear pore complex structure during skeletal myogensis (2011)
  • Author(s): Asally, M., Yasuda, Y., Oka, M., Otsuka, S., Yoshimura, S. H., Takeyasu, K. and Yoneda, Y.
  • Journal Title: FEBS J Volume: 278 Pages: 610-621
  • DOI: doi:10.1111/j.1742-4658.2010.07982.x.
  • Peer Reviewed
• [Presentation] The involvement of small GTPase Ran in cellular aging (2011)
  • Author(s): 永井理博、米田悦啓
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 20111213-16
• [Presentation] Importin alpha mediates biased translocation through nuclear pores in conjunction with Nup153 (2011)
  • Author(s): Ogawa, Y., Miyamoto, Y., Oka, M. and Yoneda, Y.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 20111213-16
• [Presentation] The mechanism to determine a nuclear transport pathway by NLS sequence (2011)
  • Author(s): Kimoto, C., Yasuhara, N. and Yoneda, Y.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 20111213-16
• [Presentation] Role of nucleocytoplasmic shuttling of estrogen receptor (2011)
  • Author(s): Moriyama, T., Oka, M. and Yoneda, Y.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 20111213-16
• [Presentation] The nucleocytoplasmic transport system regulates the stem cell differentiation (2011)
  • Author(s): Yasuhara, N., Yamagishi, R., Arai, Y., Yanagida, T., Kaneko, H. and Yoneda, Y.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(横浜市)
  • Year and Date: 20111213-16
• [Remarks]
  • URL: http://www.anat3.med.osaka-u.ac.jp/