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PMID: 15340047 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

RhoE inhibits cell cycle progression and Ras-induced transformation.

Molecular and cellular biology ·Vol. 24 ·No. 18 ·2004-09-00 ·Pages 7829-40

Villalonga P, Guasch RM, Riento K, Ridley AJ

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.

MeSH Terms
Actins/metabolism Animals Cell Cycle/physiology Cell Cycle Proteins/metabolism Cell Transformation, Neoplastic Cisplatin/pharmacology Cyclin D1/metabolism Cyclin-Dependent Kinase Inhibitor p21 Cyclins/metabolism Cytoskeleton/metabolism DNA-Binding Proteins/metabolism E2F Transcription Factors GTPase-Activating Proteins/genetics,physiology Gene Expression Regulation/drug effects Mice NIH 3T3 Cells Proto-Oncogene Proteins c-raf/physiology Recombinant Proteins/genetics,metabolism Retinoblastoma Protein/physiology Signal Transduction Transcription Factors/metabolism Transfection ras Proteins/physiology rho GTP-Binding Proteins
Chemicals
Actins Cdkn1a protein, mouse Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p21 Cyclins DNA-Binding Proteins E2F Transcription Factors GTPase-Activating Proteins Recombinant Proteins Retinoblastoma Protein Transcription Factors rho GTPase-activating protein Cyclin D1 Proto-Oncogene Proteins c-raf Rnd3 protein, mouse RND3 protein, human ras Proteins rho GTP-Binding Proteins Cisplatin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Villalonga Priam
Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House St., London W1W 7BS, United Kingdom.
Guasch Rosa M
Riento Kirsi
Ridley Anne J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.18.7829-7840.2004
Published
2004-09-00
Pages
7829-40
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC515038
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.24.18.7829-7840.2004 PMC Full Text View journal details
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