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Phosphorylation of Ezrin by Cyclin-Dependent Kinase 5 Induces the Release of Rho GDP Dissociation Inhibitor to Inhibit Rac1 Activity in Senescent Cells

Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts

Requests for reprints: Philip W. Hinds, Molecular Oncology Research Institute, Tufts-New England Medical Center, 75 Kneeland Street, Boston, MA 02111. Phone: 617-636-7947; Fax: 617-636-7813; E-mail: phinds{at}tufts-nemc.org.

Normal somatic cells enter a state of irreversible proliferation arrest-designated cellular senescence, which is characterized by biochemical changes and a distinctive morphology. Cellular stresses, including oncogene activation, can lead to senescence. Consistent with an antioncogenic role in this process, the tumor suppressor pRb plays a critical role in senescence. Reexpression of pRb in human tumor cells results in senescence-like changes, including cell cycle exit and cell shape alteration. Here, we show that pRb-induced senescent SAOS-2 cells and senescent human diploid fibroblasts are accompanied by increased phosphorylation of ezrin at T235 by cyclin-dependent kinase 5 and consequent dissociation of Rho GDP dissociation inhibitor (Rho-GDI) from an ezrin/Rho-GDI complex. The release of Rho-GDI results in increased interaction with Rac1 GTPase and inhibition of Rac1 GTPase activity. In addition, reduction of Rho-GDI by small interfering RNA in pRb-transfected cells prevented senescence-associated flat cell formation, suggesting that Rho-GDI plays an important role in contributing to cellular morphology in the process of senescence. (Cancer Res 2006; 66(5): 2708-15)

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