4.4 Article

Competitive Nuclear Export of Cyclin D1 and Hic-5 Regulates Anchorage Dependence of Cell Growth and Survival

Journal

MOLECULAR BIOLOGY OF THE CELL
Volume 20, Issue 1, Pages 218-232

Publisher

AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-04-0428

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Funding

  1. Grants-in-Aid for Scientific Research
  2. High-Technology Research Center Project
  3. Private Universities
  4. Ministry of Education, Culture, Sports, Science, and Technology (MEXT)

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Anchorage dependence of cell growth and survival is a critical trait that distinguishes nontransformed cells from transformed cells. We demonstrate that anchorage dependence is determined by anchorage-dependent nuclear retention of cyclin D1, which is regulated by the focal adhesion protein, Hic-5, whose CRM1-dependent nuclear export counteracts that of cyclin D1. An adaptor protein, PINCH, interacts with cyclin D1 and Hic-5 and potentially serves as an interface for the competition between cyclin D1 and Hic-5 for CRM1. In nonadherent cells, the nuclear export of Hic-5, which is redox-sensitive, was interrupted due to elevated production of reactive oxygen species, and cyclin D1 was exported from the nucleus. When an Hic-5 mutant that was continuously exported in a reactive oxygen species-insensitive manner was introduced into the cells, cyclin D1 was retained in the nucleus under nonadherent conditions, and a significant population of cells escaped from growth arrest or apoptosis. Interestingly, activated ras achieved predominant cyclin D1 nuclear localization and thus, growth in nonadherent cells. We report a failsafe system for anchorage dependence of cell growth and survival.

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