Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation

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 ce ll cycle, but how phosphorylation regulates redistribution has not been res olved. For example, phosphorylation of nuclear cyclin D1 could increase its rate of nuclear export relative to nuclear import; alternatively, phosphor ylation of cytoplasmic cyclin D1 by GSK-3 beta could inhibit nuclear import . Here, we report that GSK-3 beta -dependent phosphorylation promotes cycli n D1 nuclear export by facilitating the association of cyclin D1 with the n uclear exportin CRM1. D1-T286A, a cyclin D1 mutant that cannot be phosphory lated by GSK-3 beta, remains nuclear throughout the cell cycle, a consequen ce of its reduced binding to CRM1. Constitutive overexpression of the nucle ar cyclin D1-T286A in murine fibroblasts results in cellular transformation and promotes tumor growth in immune compromised mice. Thus, removal of cyc lin D1 from the nucleus during S phase appears essential for regulated cell division.