title: RhoE inhibits cell cycle progression and Ras-induced transformation.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House St., London W1W 7BS, United Kingdom.
authors.forename: Priam
authors.initials: P
authors.lastname: Villalonga
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Guasch
authors.forename: Kirsi
authors.initials: K
authors.lastname: Riento
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002945:Cisplatin / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000502:physiology*; D020741:rho GTP-Binding Proteins
chemical_list: D000199:Actins; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D020690:GTPase-Activating Proteins; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C085379:rho GTPase-activating protein; D019938:Cyclin D1; D019908:Proto-Oncogene Proteins c-raf; C513341:Rnd3 protein, mouse; C508705:RND3 protein, human; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D002945:Cisplatin