title: The Rho family member RhoE interacts with Skp2 and is degraded at the proteasome during cell cycle progression.
abstract: RhoE/Rnd3 is an atypical member of the Rho family of small GTPases. In addition to regulating actin cytoskeleton dynamics, RhoE is involved in the regulation of cell proliferation, survival, and metastasis. We examined RhoE expression levels during cell cycle and investigated mechanisms controlling them. We show that RhoE accumulates during G1, in contact-inhibited cells, and when the Akt pathway is inhibited. Conversely, RhoE levels rapidly decrease at the G1/S transition and remain low for most of the cell cycle. We also show that the half-life of RhoE is shorter than that of other Rho proteins and that its expression levels are regulated by proteasomal degradation. The expression patterns of RhoE overlap with that of the cell cycle inhibitor p27. Consistently with an involvement of RhoE in cell cycle regulation, RhoE and p27 levels decrease after overexpression of the F-box protein Skp2. We have identified a region between amino acids 231 and 240 of RhoE as the Skp2-interacting domain and Lys(235) as the substrate for ubiquitylation. Based on our results, we propose a mechanism according to which proteasomal degradation of RhoE by Skp2 regulates its protein levels to control cellular proliferation.
authors.affiliation: From the Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera, 46113-Moncada (Valencia), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Lonjedo
authors.forename: Enric
authors.initials: E
authors.lastname: Poch
authors.forename: Enric
authors.initials: E
authors.lastname: Mocholí
authors.forename: Marta
authors.initials: M
authors.lastname: Hernández-Sánchez
authors.forename: Carmen
authors.initials: C
authors.lastname: Ivorra
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Franke
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Guasch
authors.forename: Ignacio
authors.initials: I
authors.lastname: Pérez-Roger
mesh_terms: D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D054875:Ubiquitination / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D044786:S-Phase Kinase-Associated Proteins; D046988:Proteasome Endopeptidase Complex; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins
keywords: Akt; Cell Cycle; Proteasomal Degradation; Proteasome; Rho GTPases; RhoE; Skp2; Ubiquitylation; p27
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