Journal
GENES & DEVELOPMENT
Volume 14, Issue 24, Pages 3102-3114Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.854900
Keywords
cyclin D1; GSK-3 beta; CRM1; tumorigenesis; nuclear export
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Funding
- NCI NIH HHS [T32 CA09476, R01 CA076379, P30 CA36727, T32 CA009476, P30 CA036727] Funding Source: Medline
- NIDDK NIH HHS [R01 DK044158, DK44158] Funding Source: Medline
- NIGMS NIH HHS [R01 GM059213] Funding Source: Medline
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GSK-3 beta -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-3 beta could inhibit nuclear import. Here, we report that GSK-3 beta -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-3 beta, 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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