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RhoE Inhibits Cell Cycle Progression and Ras-Induced Transformation

Priam Villalonga,¹ Rosa M. Guasch,^1, Kirsi Riento,¹ and Anne J. Ridley^1,2*

Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine,¹ Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom²

Received 26 February 2004/ Returned for modification 26 March 2004/ Accepted 21 June 2004

Rho GTPases are major regulators of cytoskeletal dynamics, but they also affect cell proliferation, transformation, and oncogenesis. RhoE, a member of the Rnd subfamily that does not detectably hydrolyze GTP, inhibits RhoA/ROCK signaling to promote actin stress fiber and focal adhesion disassembly. We have generated fibroblasts with inducible RhoE expression to investigate the role of RhoE in cell proliferation. RhoE expression induced a loss of stress fibers and cell rounding, but these effects were only transient. RhoE induction inhibited cell proliferation and serum-induced S-phase entry. Neither ROCK nor RhoA inhibition accounted for this response. Consistent with its inhibitory effect on cell cycle progression, RhoE expression was induced by cisplatin, a DNA damage-inducing agent. RhoE-expressing cells failed to accumulate cyclin D1 or p21^cip1 protein or to activate E2F-regulated genes in response to serum, although ERK, PI3-K/Akt, FAK, Rac, and cyclin D1 transcription was activated normally. The expression of proteins that bypass the retinoblastoma (pRb) family cell cycle checkpoint, including human papillomavirus E7, adenovirus E1A, and cyclin E, rescued cell cycle progression in RhoE-expressing cells. RhoE also inhibited Ras- and Raf-induced fibroblast transformation. These results indicate that RhoE inhibits cell cycle progression upstream of the pRb checkpoint.

Present address: Instituto de Investigaciones Citologicas (FVIB), 46010 Valencia, Spain.

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