RhoBTB Proteins in Cancer



The most peculiar members of the Rho GTPase family are the RhoBTB proteins - large, multimodular proteins that contain two copies of the BTB protein-protein interaction module. While we know very little of the signalling pathways controlled by RhoBTBs, they are some of the oldest members of the family, predating RhoA and Cdc42. While other Rho GTPase may have critical enabling roles in cancer, the RhoBTBs show the clearest evidence for genetic alteration - with loss, mutation, and silencing of the RhoBTB2 isoform being a seemingly common event in a wide range of carcinomas. While activation of other Rho GTPase pathways can promote invasion and metastasis, the RhoBTBs appear to have a protective role and may function as tumour suppressors.


CXCL14 Expression Candidate Tumour Suppressor Promyelocytic Leukemia Zinc Finger Primary Human Bronchial Epithelial Cell Somatic Missense Mutation 
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  1. Ahmad KF, Engel CK, Prive GG (1998) Crystal structure of the BTB domain from PLZF. Proc Natl Acad Sci U S A 95:12123–12128.CrossRefPubMedGoogle Scholar
  2. Allinen M, Beroukhim R, Cai L, et al (2004) Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6: 17–32.CrossRefPubMedGoogle Scholar
  3. Aspenstrom P, Fransson A, Saras J (2004) Rho GTPases have diverse effects on the organization of the actin filament system. Biochem J 377:327–337.CrossRefPubMedGoogle Scholar
  4. Beder LB, Gunduz M, Ouchida M, et al (2003) Genome-wide analyses on loss of heterozygosity in head and neck squamous cell carcinomas. Lab Invest 83:99–105.PubMedGoogle Scholar
  5. Beder LB, Gunduz M, Ouchida M, et al (2006) Identification of a candidate tumor suppressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer. J Cancer Res Clin Oncol 132:19–27.CrossRefPubMedGoogle Scholar
  6. Boureux A, Vignal E, Faure S, Fort P (2007) Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol 24:203–216.CrossRefPubMedGoogle Scholar
  7. Chang FK, Sato N, Kobayashi-Simorowski N, Yoshihara T, Meth JL, Hamaguchi M (2006) DBC2 is essential for transporting vesicular stomatitis virus glycoprotein. J Mol Biol 364:302–308.CrossRefPubMedGoogle Scholar
  8. Chardin P (2006) Function and regulation of Rnd proteins. Nat Rev Mol Cell Biol 7:54–62.CrossRefPubMedGoogle Scholar
  9. Cho YG, Choi BJ, Kim CJ et al (2007) Genetic analysis of the DBC2 gene in gastric cancer. Acta Oncol 28:1–6.Google Scholar
  10. Forbes S, Clements J, Dawson E et al (2006) Cosmic 2005. Br J Cancer 94:318–322.Google Scholar
  11. Frederick MJ, Henderson Y, Xu X et al (2000) In vivo expression of the novel CXC chemokine BRAK in normal and cancerous human tissue. Am J Pathol 156:1937–1950.PubMedGoogle Scholar
  12. Freeman SN, Ma Y, Cress WD (2008) RhoBTB2 (DBC2) Is a Mitotic E2F1 Target Gene with a Novel Role in Apoptosis. J Biol Chem 283:2353–2362.CrossRefPubMedGoogle Scholar
  13. Hamaguchi M, Meth JL, von Klitzing C et al (2002) DBC2, a candidate for a tumor suppressor gene involved in breast cancer. Proc Natl Acad Sci U S A 99:13647–13652.CrossRefPubMedGoogle Scholar
  14. Jardin F, Sahota SS (2005) Targeted somatic mutation of the BCL6 proto-oncogene and its impact on lymphomagenesis. Hematology 10:115–129.CrossRefPubMedGoogle Scholar
  15. Knowles MA, Aveyard JS, Taylor CF, Harnden P, Bass S (2005) Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer. Cancer Lett 225:121–130.CrossRefPubMedGoogle Scholar
  16. Kurth I, Willimann K, Schaerli P, Hunziker T, Clark-Lewis I, Moser B (2001) Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development. J Exp Med 194:855–861.CrossRefPubMedGoogle Scholar
  17. McConnell MJ, Licht JD (2007) The PLZF gene of t (11;17)-associated APL. Curr Top Microbiol Immunol 313:31–48.CrossRefPubMedGoogle Scholar
  18. Ohadi M, Totonchi M, Maguire P et al (2007). Mutation analysis of the DBC2 gene in sporadic and familial breast cancer. Acta Oncol 46:770–772.CrossRefPubMedGoogle Scholar
  19. Paduch M, Jelen F, Otlewski J (2001) Structure of small G proteins and their regulators. Acta Biochim Pol 48:829–850.PubMedGoogle Scholar
  20. Pellegrin S, Mellor H (2006) Evolution of the human Rho GTPase family – Conservation and diversity. In: Manser E (ed) RHO family GTPases, vol. 3. Springer, Netherlands, pp. 19–29.CrossRefGoogle Scholar
  21. Perez-Torrado R, Yamada D, Defossez PA (2006) Born to bind: the BTB protein-protein interaction domain. Bioessays 28:1194–1202.CrossRefPubMedGoogle Scholar
  22. Philips A, Blein M, Robert A et al (2003) Ascidians as a vertebrate-like model organism for physiological studies of Rho GTPase signaling. Biol Cell 95:295–302.CrossRefPubMedGoogle Scholar
  23. Pintard L, Willems A, Peter M (2004) Cullin-based ubiquitin ligases: Cul3-BTB complexes join the family. Embo J 23:1681–1687.CrossRefPubMedGoogle Scholar
  24. Pintard L, Willis JH, Willems A et al (2003) The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 425:311–316.CrossRefPubMedGoogle Scholar
  25. Ramos S, Khademi F, Somesh BP, Rivero F (2002) Genomic organization and expression profile of the small GTPases of the RhoBTB family in human and mouse. Gene 298:147–157.CrossRefPubMedGoogle Scholar
  26. Rivero F, Dislich H, Glockner G, Noegel AA (2001) The Dictyostelium discoideum family of Rho-related proteins. Nucleic Acids Res 29:1068–1079.CrossRefPubMedGoogle Scholar
  27. Shellenberger TD, Wang M, Gujrati M et al (2004) BRAK/CXCL14 is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells. Cancer Res 64:8262–8270.CrossRefPubMedGoogle Scholar
  28. Shurin GV, Ferris RL, Tourkova IL et al (2005) Loss of new chemokine CXCL14 in tumor tissue is associated with low infiltration by dendritic cells (DC), while restoration of human CXCL14 expression in tumor cells causes attraction of DC both in vitro and in vivo. J Immunol 174:5490–5498.PubMedGoogle Scholar
  29. Siripurapu V, Meth J, Kobayashi N, Hamaguchi M (2005) DBC2 significantly influences cell-cycle, apoptosis, cytoskeleton and membrane-trafficking pathways. J Mol Biol 346:83–89.CrossRefPubMedGoogle Scholar
  30. Starnes T, Rasila KK, Robertson MJ et al (2006) The chemokine CXCL14 (BRAK) stimulates activated NK cell migration: implications for the downregulation of CXCL14 in malignancy. Exp Hematol 34:1101–1105.CrossRefPubMedGoogle Scholar
  31. Stogios PJ, Downs GS, Jauhal JJ, Nandra SK, Prive GG (2005) Sequence and structural analysis of BTB domain proteins. Genome Biol 6:R82.CrossRefPubMedGoogle Scholar
  32. Wilkins A, Ping Q, Carpenter CL (2004) RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligase complex. Genes Dev 18:856–861.CrossRefPubMedGoogle Scholar
  33. Yoshihara T, Collado D, Hamaguchi M (2007) Cyclin D1 down-regulation is essential for DBC2’s tumor suppressor function. Biochem Biophys Res Commun 358:1076–1079.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of BiochemistrySchool of Medical Sciences, University of Bristol, University WalkBristolUK

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