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Vol. 20, Issue 1, 218-232, January 1, 2009

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

Department of Microbiology, Showa University School of Pharmaceutical Sciences, Tokyo 142-8555, Japan

Submitted April 25, 2008; Revised October 7, 2008; Accepted October 9, 2008
Monitoring Editor: Martin A. Schwartz

InCytes from MBC

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.

Address correspondence to: Motoko Shibanuma (smotoko{at}pharm.showa-u.ac.jp).

Abbreviations used: BrdU, 5-bromo-2'-deoxyuridine; CDK, cyclin-dependent kinase; DAPI, 4'6-diamidino-2-phenylindole; ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; FA, focal adhesions; FAK, focal adhesion kinase; GSK, glycogen synthase kinase; ILK, integrin-linked kinase; LMB, leptomycin B; MEF, mouse embryo fibroblast; NLS, nuclear localization signal; PDTC, pyrrolidine dithiocarbamate; PINCH, particularly interesting new Cys-His protein; PTP-PEST, protein-tyrosine phosphatase PEST; ROS, reactive oxygen species; tiron, 1,2-dihidroxybenzene-3,5-disulphonic acid.