Cytoplasmic-Nuclear Trafficking of G1/S Cell Cycle Molecules and Adult Human 13-Cell Replication A Revised Model of Human β-Cell G1/S Control

Harnessing control of human beta-cell proliferation has proven frustratingly difficult Most G1/S control molecules, generally presumed to be nuclear proteins in the human beta-cell, are in fact constrained to the cytoplasm. Here, we asked whether G1/S molecules might traffic into and out of the cytoplasmic compartment in association with activation of cell cycle progression. Cdk6 and cyclin D3 were used to drive human beta-cell proliferation and promptly translocated into the nucleus in association with proliferation. In contrast, the cell cycle inhibitors p15, p18, and p19 did not alter their location, remaining cytoplasmic. Conversely, p16, p21, and p27 increased their nuclear frequency. In contrast once again, p57 decreased its nuclear frequency. Whereas proliferating beta-cells contained nuclear cyclin D3 and cdk6, proliferation generally did not occur in beta-cells that contained nuclear cell cycle inhibitors, except p21. Dynamic cytoplasmic-nuclear trafficking of cdk6 was confirmed using green fluorescent protein tagged cdk6 and live cell imaging. Thus, we provide novel working models describing the control of cell cycle progression in the human beta-cell. In addition to known obstacles to beta-cell proliferation, cytoplasmic-to-nuclear trafficking of G1/S molecules may represent an obstacle as well as a therapeutic opportunity for human beta-cell expansion.