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Mechanism of Cell Cycle Regulation by FIP200 in Human Breast Cancer Cells

Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, New York

Requests for reprints: Jun-Lin Guan, Department of Molecular Medicine, C4-177 VMC Cornell University College of Veterinary Medicine, Ithaca, NY 14853. Phone: 607-253-3586; Fax: 607-253-3708; E-mail: jg19{at}cornell.edu.

FIP200 is a novel protein inhibitor for focal adhesion kinase (FAK), which binds to FAK directly and inhibits its kinase activity and associated cellular functions, such as cell adhesion, spreading, and motility in fibroblasts. Here we show that FIP200 inhibits G₁-S phase progression, proliferation, and clonogenic survival in human breast cancer cells. Consistent with the G₁ arrest induced by FIP200, we found that FIP200 increased p21 and decreased cyclin D1 protein levels in breast cancer cells. In addition, FIP200 significantly induced p21 promoter activity in MCF-7 cells and this response was abolished upon deletion of p53 binding sites within p21 promoter. Furthermore, we found that FIP200 could interact with exogenous and endogenous p53 protein and significantly increase its half-life compared with the control cells. We also found that the NH₂-terminal 154 residues of FIP200 were sufficient to mediate p53 interaction and G₁ arrest in cells. The increase in p53 half-life correlated with the increased phosphorylation at Ser¹⁵ and decreased proteasomal degradation via ubiquitin and Hdm2-independent mechanism. Stabilization of p53 by FIP200 could be partially reversed by NQO1 inhibitor, dicoumarol. In contrast to p53, FIP200 decreased cyclin D1 protein half-life by promoting proteasome-dependent degradation of cyclin D1. In summary, our results suggest that FIP200 increases p21 protein levels via stabilization of its upstream regulator p53 and decreases cyclin D1 protein by promoting its degradation. Both effects are critical for FIP200-induced G₁ arrest and may contribute to the putative antitumor activities of FIP200 in breast cancer.

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