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FoxO1a Can Alter Cell Cycle Progression by Regulating the Nuclear Localization of p27^kip in Granulosa Cells

Department of Medicine, The Pennsylvania State University, College of Medicine, Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: James Hammond, The Pennsylvania State University, College of Medicine, 500 University Drive, C6636, Hershey, Pennsylvania 17033. E-mail: jhammond{at}psu.edu

Forkhead transcription factors of the FOXO family are important downstream targets of the phosphatidylinositol 3-kinase pathway, which has been shown to play a critical role in cell proliferation and cell survival. Activation of FOXOs can block cellular proliferation and drive cells into a quiescent state. In certain cell types, this cell cycle arrest is dependent on the transcriptional induction of the cell-cycle inhibitor p27^kip. In granulosa cells, which go through an exponential growth phase during development of the ovarian follicle, we find that FoxO1a is a key regulator of the G1/S transition in these cells. Overexpression of a dominant-negative version of FoxO1a (Foxo1a-256; a C-terminal truncation mutant that possesses a functional DNA-binding domain, but lacks a transactivation domain) causes a dramatic increase in S-phase cells (>8-fold increase by both DNA content and bromodeoxyuridine incorporation assays). Surprisingly, this is not dependent on transactivation of the p27^kip gene. We provide evidence that when FoxO1a activity is impeded, p27^kip protein is largely localized to the cytosol, suggesting that FoxO1a blocks cell cycle entry by altering the compartmentalization of p27^kip within the cell, increasing its concentration in the nucleus. These studies demonstrate for the first time that FoxO1a can regulate p27^kip nuclear localization.

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