Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1–dependent cellular transformation
- 1Eppley Institute for Research in Cancer and Allied Diseases, Departments of 2Pathology and Microbiology, and 3Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA; 4Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA; 5Department of Biochemistry, University of Missouri–Columbia, Columbia, Missouri 65211, USA
Abstract
GSK-3β-dependent phosphorylation of cyclin D1 at Thr-286 promotes the nuclear-to-cytoplasmic redistribution of cyclin D1 during S phase of the cell cycle, but how phosphorylation regulates redistribution has not been resolved. For example, phosphorylation of nuclear cyclin D1 could increase its rate of nuclear export relative to nuclear import; alternatively, phosphorylation of cytoplasmic cyclin D1 by GSK-3β could inhibit nuclear import. Here, we report that GSK-3β-dependent phosphorylation promotes cyclin D1 nuclear export by facilitating the association of cyclin D1 with the nuclear exportin CRM1. D1-T286A, a cyclin D1 mutant that cannot be phosphorylated by GSK-3β, remains nuclear throughout the cell cycle, a consequence of its reduced binding to CRM1. Constitutive overexpression of the nuclear cyclin D1-T286A in murine fibroblasts results in cellular transformation and promotes tumor growth in immune compromised mice. Thus, removal of cyclin D1 from the nucleus during S phase appears essential for regulated cell division.
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Footnotes
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↵6 Corresponding author.
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E-MAIL adiehl{at}unmc.edu; FAX (402) 559-4651.
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Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.854900.
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- Received September 27, 2000.
- Accepted November 2, 2000.
- Cold Spring Harbor Laboratory Press
