RHOBTB1 (Rho-related BTB domain containing 1)

	Gene structure of RHOBTB1. Boxes represent exons. The coding region is represented in blue. For simplicity very large introns in the 5'UTR have been shortened (indicated by discontinuous lines)
Description	The RHOBTB1 gene spans over 132 Kbp genomic DNA and consists of 14 exons, 9 coding exons and 5 more exons in the 5'UTR (Figure 1). The coding sequence of RHOBTB1 is 2091 nucleotides long (Ramos et al., 2002). The promoter region has a high GC content with numerous CpG islands. The RHOBTB1 locus has binding sites for retinoid X receptor and PPARA (peroxisome proliferator-activated receptor- α, as demonstrated by chromatin immunoprecipitation (Pelham et al., 2012).
Transcription	Based on EST sequence analyses there are transcription variants that arise from the use of alternative promoters and alternative splicing, but none of the transcripts affects the coding region.

Note	RhoBTB1 is one of the three members of the RhoBTB family in vertebrates. The RhoBTB family was identified during the study of the genes encoding Rho-related proteins in the lower eukaryote Dictyostelium discoideum (Rivero et al., 2002). All three RhoBTB proteins may be implicated in tumorigenesis.
	Architecture of RhoBTB proteins. The figure shows the three human (Hs) RhoBTB subfamily members as well as the Drosophila (Dm) and Dictyostelium (Dd) orthologues. The simplified phylogenetic tree on the left illustrates the relationship among the proteins (overall percentage similarity between branches). The different domains are indicated with colours.
Description	RhoBTB1 is 696 amino acids long. All RhoBTB proteins share the same domain architecture: a GTPase domain is followed by a proline-rich region, a tandem of two BTB domains and a C-terminal region (Figure 2). The GTPase domain is Rho-related and contains a Rho insert that is longer than usual, two insertions and one deletion, as well as a few deviations from the GTPase consensus of most Rho GTPases. In analogy to RhoBTB2, the GTPase domain of RhoBTB1 is likely to bind GTP (Manjarrez et al., 2014). The proline-rich region links the GTPase to the first BTB domain. This region could act as a SH3 domain-binding site. The BTB domain (broad complex, tramtract and bric-a-brac) is an evolutionary conserved protein-protein interaction domain that participates in homomeric and heteromeric associations with other BTB domains. The BTB domain was also identified as a component of multimeric cullin3-dependent ubiquitin ligase complexes. The first BTB domain is bipartite, being interrupted by an insertion of unknown function. The BTB domains of RhoBTB allow the formation of homodimers and of heterodimers with other proteins of the RhoBTB family (Berthold et al., 2008). The C-terminus is a region conserved in all members of the RhoBTB subfamily. It predictably folds as 4 consecutive alpha-helices and one beta-strand and may constitute a RING finger domain (Manjarrez et al., 2014). Many RING finger domains function as ubiquitin ligases. RhoBTB1 does not bear a CAAX motif that is typical for classical Rho GTPases and serves for localization of the protein to membranes.
Expression	RHOBTB1 is ubiquitously expressed, with high levels detected in skeletal muscle, placenta, stomach, kidney, testis, ovary, uterus and adrenal gland. The gene is also expressed in foetal tissues (Ramos et al., 2002; Nagase et al., 1998). Expression of RHOBTB1 has been found decreased in kidney, breast and stomach tumors in a cancer profiling array (Berthold et al., 2008), in 37% of 46 head and neck squamous cell carcinomas (Beder et al., 2006) and in colon cancer tissues (Xu et al., 2013). RHOBTB1 is a target of the microRNA MIR31- (Alder et al., 2012; Xu et al., 2013).
Localisation	The localisation of endogenous RhoBTB1 has not been investigated. In cells expressing RhoBTB1 ectopically the protein tends to form aggregates in the cytoplasm (Aspenström et al., 2004).
Function	RHOBTB1 has been proposed as a candidate tumour suppressor gene (Beder et al., 2006). The mechanisms by which RhoBTB proteins in general exert this and other roles remain speculative. Much of what we know about RhoBTB2 may be made extensive to RhoBTB1 because of their similarity. RhoBTB1 binds to cullin3 and by analogy to RhoBTB2 and RhoBTB3 may constitute ubiquitin ligase complexes. RhoBTB proteins appear to exist in an inactive state through an intramolecular interaction of the BTB domain region with the GTPase domain (Berthold et al., 2008). This model has been refined recently for RhoBTB2 to show that the HSP90AA1 (Hsp90) chaperone machinery unlocks RhoBTB, enabling GTP binding and interaction with Cullin 3 and the COPS8 (COP9) signalosome. COP9 deneddylates Cullin 3 and stabilizes the complex (Manjarrez et al. 2014). Considering the high degree of similarity between RhoBTB2 and RhoBTB1, this mechanism is very likely to apply to RhoBTB1 too. RHOBTB1 has been identified as a target gene of the nuclear hormone receptor PPARG. RhoBTB1 mRNA and protein levels are decreased in the aorta of mice expressing a dominant negative PPARG. These mice also present a concomitant decrease in Cullin 3, and it has been proposed that RhoBTB1 regulates Cullin 3 levels or activity, which in turn regulates RHOA. turnover in smooth muscle. RhoBTB1 emerges as a component of a signaling mechanism that regulates vascular function and blood pressure (Pelham et al., 2012). RhoBTB1, like RhoBTB2, is required for expression of the chemokine CXCL14 in keratinocytes independently of Cullin3-mediated protein degradation (McKinnon et al., 2008). RhoBTB1 displays only a moderate influence on the morphology and actin organisation of porcine aortic endothelial cells upon ectopic expression. It does not interact with the GTPase-binding domain of WASP, PAK1 or RTKN (Rhotekin), which are well-known effectors of many typical Rho GTPases (Aspenstrom et al., 2004). RhoBTB1, like RhoBTB2 and RhoBTB3, interacts with LLRC41 (leucine rich repeat containing 41, MUF1). MUF-1 is a nuclear protein and carries a BC-box that functions as a linker in multicomponent Cullin 5-dependent ubiquitin ligase complexes (Schenková et al., 2012). MUF1 may be a substrate for RhoBTB-Cullin 3 ubiquitin ligase complexes. The function of MUF1 is unknown, but it is suspected to be involved in the DNA damage response
Homology	There are three RhoBTB proteins in vertebrates: RhoBTB1, RhoBTB2 and RhoBTB3 (Figure 2). RhoBTB1 is very similar to RhoBTB2, while RhoBTB3 displays very low similarity to these. Orthologues have been found in amoebae and in insects but they are absent in plants and fungi.

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