Acta Pharmacologica Sinica 2008 March; 29 (3): 285-295; doi: 10.1111/j.1745-7254.2008.00773.x

 
Review
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Rho GTPases of the RhoBTB subfamily and tumorigenesis1
 

Jessica BERTHOLD2, Kristína SCHENKOVÁ2, Francisco RIVERO2,3,4

2Centers for Biochemistry and Molecular Medicine, University of Cologne, Cologne, Germany; 3The Hull York Medical School, University of Hull, Hull HU6 7RX, UK

 

RhoBTB proteins constitute a subfamily of atypical members within the Rho family of small guanosine triphosphatases (GTPases). Their most salient feature is their domain architecture: a GTPase domain (in most cases, non-functional) is followed by a proline-rich region, a tandem of 2 broad-complex, tramtrack, bric à brac (BTB) domains, and a conserved C-terminal region. In humans, the RhoBTB subfamily consists of 3 isoforms: RhoBTB1, RhoBTB2, and RhoBTB3. Orthologs are present in several other eukaryotes, such as Drosophila and Dictyostelium, but have been lost in plants and fungi. Interest in RhoBTB arose when RHOBTB2 was identified as the gene homozygously deleted in breast cancer samples and was proposed as a candidate tumor suppressor gene, a property that has been extended to RHOBTB1. The functions of RhoBTB proteins have not been defined yet, but may be related to the roles of BTB domains in the recruitment of cullin3, a component of a family of ubiquitin ligases. A model emerges in which RhoBTB proteins are required to maintain constant levels of putative substrates involved in cell cycle regulation or vesicle transport through targeting for degradation in the 26S proteasome. RhoBTB proteins are engrossing the list of Rho GTPases involved in tumorigenesis. Unlike typical Rho GTPases (usually overexpressed or hyperactive), RhoBTB proteins appear to play a part in the carcinogenic process through a mechanism that involves the decreased or abolished expression of the corresponding genes, or more rarely, mutations that result in impaired functioning of the protein, presumably leading to the accumulation of RhoBTB substrates and alterations of the cellular homeostasis.

 

Keywords: Rho guanosine triphosphatase; RhoBTB; DBC2; cullin; neoplasm

 
1 This work was supported by grants from the Center for Molecular Medicine Cologne, the Deutsche Forschungsgemeinschaft, and the Köln Fortune Program of the Medical Faculty, University of Cologne.

4 Correspondence to Dr Francisco RIVERO.
Phn 49-221-478-6987.
Fax 49-221-478-6979.
E-mail Francisco.rivero@hyms.ac.uk
Received 2007-11-17     Accepted 2007-12-16

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