Abstract
RhoE is a small GTPase involved in the regulation of actin cytoskeleton dynamics, cell cycle and apoptosis. The role of RhoE in cancer is currently controversial, with reports of both oncogenic and tumor-suppressive functions for RhoE. Using RhoE-deficient mice, we show here that the absence of RhoE blunts contact-inhibition of growth by inhibiting p27Kip1 nuclear translocation and cooperates in oncogenic transformation of mouse primary fibroblasts. Heterozygous RhoE+/gt mice are more susceptible to chemically induced skin tumors and RhoE knock-down results in increased metastatic potential of cancer cells. These results indicate that RhoE plays a role in suppressing tumor initiation and progression.
Highlights
RhoE/Rnd3 is an atypical member of the Rho family of proteins that negatively regulates the RhoA-ROCK pathway [1,2,3,4,5]
In order to test the role of RhoE in the control of cell proliferation, we analyzed the growth of primary Mouse Embryo Fibroblasts (MEFs) from RhoE deficient mice (RhoEgt/gt) as well as from wild-type (RhoE+/+) and hemizygous (RhoE+/gt) animals
We measured the cell density reached by primary fibroblasts from RhoEgt/gt and RhoE+/gt mouse embryos kept in culture for 15 days and compared it to that of RhoE+/+ cells
Summary
RhoE/Rnd is an atypical member of the Rho family of proteins that negatively regulates the RhoA-ROCK pathway [1,2,3,4,5]. RhoE overexpression inhibits cellular proliferation, blocking the cell cycle in G1 [6,7,8,9]. RhoE is regulated along the cell cycle, accumulating in G1 and being rapidly degraded at the G1/S transition in a proteasome-dependent manner, and it accumulates in primary fibroblasts reaching confluency [9]. The role of RhoE in cancer is not clear at present. Some reports suggest a possible tumor suppressor role for RhoE in human cancer and metastasis [7, 1219]. Additional evidence suggests a positive correlation between RhoE expression and malignancy [20,21,22,23,24,25,26]
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