Skip to main content

Advertisement

SpringerLink
Log in

Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Rho GTPases are highly conserved proteins that play critical roles in many cellular processes including actin dynamics, vesicular trafficking, gene transcription, cell-cycle progression, and cell adhesion. The main mode of regulation of Rho GTPases is through guanine nucleotide binding (cycling between an active GTP-bound form and an inactive GDP-bound form), but transcriptional, post-transcriptional, and post-translational modes of Rho regulation have also been described. In the present review, we summarize recent progress on the mechanisms that control the expression of the three members of the Rho-like subfamily (RhoA, RhoB, and RhoC) at the level of gene transcription as well as their post-transcriptional regulation by microRNAs. We also discuss the progress made in deciphering the mechanisms of cross-talk between Rho proteins and the transforming growth factor β signaling pathway and their implications for the pathogenesis of human diseases such as cancer metastasis and fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ATF-1:

Activating transcription factor 1

BSMs:

Bronchial smooth muscles

PKG:

cGMP-dependent protein kinase

EC:

Endometrial carcinoma

EMT:

Epithelial-to-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FTIs:

Farnesyltransferase inhibitors

GGTIs:

Geranylgeranyltransferase I inhibitors

GAPs:

GTPase-activating proteins

GDIs:

Guanosine nucleotide dissociation inhibitors

GEFs:

Guanosine nucleotide exchange factors

HCC:

Hepatocellular carcinoma

HDAC1:

Histone deacetylase 1

HOXD10:

Homeobox D10

HIF:

Hypoxia inducible factor

IL-13:

Interleukin 13

miRNAs:

MicroRNAs

MAPK:

Mitogen-activated protein kinase

Miz1:

Myc-interacting zinc finger protein 1

NO:

Nitric oxide

NF-κB:

Nuclear factor kappa B

NF-Y:

Nuclear factor Y

PARP-1:

Poly(ADP-ribose) polymerase-1

PMA:

Phorbol-12-myristyl-13-acetate

ROS:

Reactive oxygen species

STAT6:

Signal transducer and activator of transcription 6

siRNAs:

Small interfering RNAs

Skp2:

S-phase kinase-associated protein 2

SDF-1:

Stromal cell-derived factor-1

TGFβ:

Transforming growth factor β

TNFα:

Tumor necrosis factor α

References

  1. Bishop AL, Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348(Pt 2):241–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vega FM, Ridley AJ (2008) Rho GTPases in cancer cell biology. FEBS Lett 582:2093–2101

    Article  CAS  PubMed  Google Scholar 

  3. Hall A, Nobes CD (2000) Rho GTPases: molecular switches that control the organization and dynamics of the actin cytoskeleton. Philos Trans R Soc Lond B Biol Sci 355:965–970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Haga RB, Ridley AJ (2016) Rho GTPases: regulation and roles in cancer cell biology. Small GTPases 7:207–221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hodge RG, Ridley AJ (2016) Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol 17:496–510

    Article  CAS  PubMed  Google Scholar 

  6. Lawson CD, Ridley AJ (2018) Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol 217: 447–457

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Schaefer A, Reinhard NR, Hordijk PL (2014) Toward understanding RhoGTPase specificity: structure, function and local activation. Small GTPases 5:6

    Article  PubMed  Google Scholar 

  8. Arthur WT, Ellerbroek SM, Der CJ, Burridge K, Wennerberg K (2002) XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC. J Biol Chem 277:42964–42972

    Article  CAS  PubMed  Google Scholar 

  9. Sloan CM, Quinn CV, Peters JP, Farley J, Goetzinger C, Wernli M, DeMali KA, Ellerbroek SM (2012) Divergence of Rho residue 43 impacts GEF activity. Small GTPases 3:15–22

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hamel B, Monaghan-Benson E, Rojas RJ, Temple BR, Marston DJ, Burridge K, Sondek J (2011) SmgGDS is a guanine nucleotide exchange factor that specifically activates RhoA and RhoC. J Biol Chem 286:12141–12148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ridley AJ, Self AJ, Kasmi F, Paterson HF, Hall A, Marshall CJ, Ellis C (1993) rho family GTPase activating proteins p190, bcr and rhoGAP show distinct specificities in vitro and in vivo. EMBO J 12:5151–5160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lazarini M et al (2013) ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells. Biochim Biophys Acta 1832:365–374

    Article  CAS  PubMed  Google Scholar 

  13. Cannizzaro LA, Madaule P, Hecht F, Axel R, Croce CM, Huebner K (1990) Chromosome localization of human ARH genes, a ras-related gene family. Genomics 6:197–203

    Article  CAS  PubMed  Google Scholar 

  14. Karnoub AE, Symons M, Campbell SL, Der CJ (2004) Molecular basis for Rho GTPase signaling specificity. Breast Cancer Res Treat 84:61–71

    Article  CAS  PubMed  Google Scholar 

  15. Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J Cell Sci 118:843–846

    Article  CAS  PubMed  Google Scholar 

  16. Kardassis D, Murphy C, Fotsis T, Moustakas A, Stournaras C (2009) Control of transforming growth factor beta signal transduction by small GTPases. FEBS J 276:2947–2965

    Article  CAS  PubMed  Google Scholar 

  17. Papadimitriou E, Kardassis D, Moustakas A, Stournaras C (2011) TGFbeta-induced early activation of the small GTPase RhoA is Smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2. Cell Physiol Biochem 28:229–238

    Article  CAS  PubMed  Google Scholar 

  18. Papadimitriou E, Vasilaki E, Vorvis C, Iliopoulos D, Moustakas A, Kardassis D, Stournaras C (2012) Differential regulation of the two RhoA-specific GEF isoforms Net1/Net1A by TGF-beta and miR-24: role in epithelial-to-mesenchymal transition. Oncogene 31:2862–2875

    Article  CAS  PubMed  Google Scholar 

  19. Vardouli L, Moustakas A, Stournaras C (2005) LIM-kinase 2 and cofilin phosphorylation mediate actin cytoskeleton reorganization induced by transforming growth factor-beta. J Biol Chem 280:11448–11457

    Article  CAS  PubMed  Google Scholar 

  20. Vardouli L, Vasilaki E, Papadimitriou E, Kardassis D, Stournaras C (2008) A novel mechanism of TGFbeta-induced actin reorganization mediated by Smad proteins and Rho GTPases. FEBS J 275:4074–4087

    Article  CAS  PubMed  Google Scholar 

  21. Vasilaki E, Papadimitriou E, Tajadura V, Ridley AJ, Stournaras C, Kardassis D (2010) Transcriptional regulation of the small GTPase RhoB gene by TGFβ-induced signaling pathways. FASEB J 24:891–905

    Article  CAS  PubMed  Google Scholar 

  22. Jansen S, Gosens R, Wieland T, Schmidt M (2018) Paving the Rho in cancer metastasis: Rho GTPases and beyond. Pharmacol Ther 183:1–21

    Article  CAS  PubMed  Google Scholar 

  23. Wang K et al (2014) Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet 46:573–582

    Article  CAS  PubMed  Google Scholar 

  24. Kakiuchi M et al (2014) Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet 46:583–587

    Article  CAS  PubMed  Google Scholar 

  25. Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513:202–209

    Article  CAS  Google Scholar 

  26. Richter J et al (2012) Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet 44:1316–1320

    Article  CAS  PubMed  Google Scholar 

  27. Yoo HY et al (2014) A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet 46:371–375

    Article  CAS  PubMed  Google Scholar 

  28. Bellizzi A et al (2008) RhoA protein expression in primary breast cancers and matched lymphocytes is associated with progression of the disease. Int J Mol Med 22:25–31

    CAS  PubMed  Google Scholar 

  29. Faried A, Faried LS, Usman N, Kato H, Kuwano H (2007) Clinical and prognostic significance of RhoA and RhoC gene expression in esophageal squamous cell carcinoma. Ann Surg Oncol 14:3593–3601

    Article  PubMed  Google Scholar 

  30. Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, Nikaido T, Konishi I (2003) Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Lab Invest 83:861–870

    Article  CAS  PubMed  Google Scholar 

  31. Lang P, Gesbert F, Delespine-Carmagnat M, Stancou R, Pouchelet M, Bertoglio J (1996) Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. EMBO J 15:510–519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen Y et al (2009) Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement. Mol Cell 35:841–855

    Article  CAS  PubMed  Google Scholar 

  33. Alberts AS, Qin H, Carr HS, Frost JA (2005) PAK1 negatively regulates the activity of the Rho exchange factor NET1. J Biol Chem 280:12152–12161

    Article  CAS  PubMed  Google Scholar 

  34. Callow MG, Zozulya S, Gishizky ML, Jallal B, Smeal T (2005) PAK4 mediates morphological changes through the regulation of GEF-H1. J Cell Sci 118:1861–1872

    Article  CAS  PubMed  Google Scholar 

  35. Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM (2004) p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev 18:862–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chan CH et al (2010) Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol 12:457–467

    Article  CAS  PubMed  Google Scholar 

  37. Adhikary S, Eilers M (2005) Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol 6:635–645

    Article  CAS  PubMed  Google Scholar 

  38. Goto K, Chiba Y, Matsusue K, Hattori Y, Maitani Y, Sakai H, Kimura S, Misawa M (2010) The proximal STAT6 and NF-kappaB sites are responsible for IL-13- and TNF-alpha-induced RhoA transcriptions in human bronchial smooth muscle cells. Pharmacol Res 61:466–472

    Article  CAS  PubMed  Google Scholar 

  39. Chiba Y, Goto K, Matsusue K, Kimura S, Misawa M (2010) Identification and characterization of rat RhoA gene promoter. J Pharmacol Sci 112:467–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shen DW, Su A, Liang XJ, Pai-Panandiker A, Gottesman MM (2004) Reduced expression of small GTPases and hypermethylation of the folate binding protein gene in cisplatin-resistant cells. Br J Cancer 91:270–276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shen DW, Pouliot LM, Gillet JP, Ma W, Johnson AC, Hall MD, Gottesman MM (2012) The transcription factor GCF2 is an upstream repressor of the small GTPAse RhoA, regulating membrane protein trafficking, sensitivity to doxorubicin, and resistance to cisplatin. Mol Pharm 9:1822–1833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Somlyo AP, Somlyo AV (2000) Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 522(Pt 2):177–185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sauzeau V, Rolli-Derkinderen M, Marionneau C, Loirand G, Pacaud P (2003) RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activation. J Biol Chem 278:9472–9480

    Article  CAS  PubMed  Google Scholar 

  44. Bhavsar PJ, Infante E, Khwaja A, Ridley AJ (2013) Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration. Oncogene 32:198–208

    Article  CAS  PubMed  Google Scholar 

  45. Luis-Ravelo D et al (2014) RHOB influences lung adenocarcinoma metastasis and resistance in a host-sensitive manner. Mol Oncol 8:196–206

    Article  CAS  PubMed  Google Scholar 

  46. Forget MA, Desrosiers RR, Del M, Moumdjian R, Shedid D, Berthelet F, Beliveau R (2002) The expression of rho proteins decreases with human brain tumor progression: potential tumor markers. Clin Exp Metastasis 19:9–15

    Article  CAS  PubMed  Google Scholar 

  47. Ma Y, Gong Y, Cheng Z, Loganathan S, Kao C, Sarkaria JN, Abel TW, Wang J (2015) Critical functions of RhoB in support of glioblastoma tumorigenesis. Neuro Oncol 17:516–525

    Article  CAS  PubMed  Google Scholar 

  48. Huang M, Prendergast GC (2006) RhoB in cancer suppression. Histol Histopathol 21:213–218

    CAS  PubMed  Google Scholar 

  49. Wang S et al (2003) Histone deacetylase 1 represses the small GTPase RhoB expression in human nonsmall lung carcinoma cell line. Oncogene 22:6204–6213

    Article  CAS  PubMed  Google Scholar 

  50. Papadopoulou N, Charalampopoulos I, Alevizopoulos K, Gravanis A, Stournaras C (2008) Rho/ROCK/actin signaling regulates membrane androgen receptor induced apoptosis in prostate cancer cells. Exp Cell Res 314:3162–3174

    Article  CAS  PubMed  Google Scholar 

  51. Papadopoulou N, Papakonstanti EA, Kallergi G, Alevizopoulos K, Stournaras C (2009) Membrane androgen receptor activation in prostate and breast tumor cells: molecular signaling and clinical impact. IUBMB Life 61:56–61

    Article  CAS  PubMed  Google Scholar 

  52. Lang F, Alevizopoulos K, Stournaras C (2013) Targeting membrane androgen receptors in tumors. Expert Opin Ther Targets 17:951–963

    Article  CAS  PubMed  Google Scholar 

  53. Stournaras C, Gravanis A, Margioris AN, Lang F (2014) The actin cytoskeleton in rapid steroid hormone actions. Cytoskeleton (Hoboken) 71:285–293

    Article  CAS  Google Scholar 

  54. Fritz G, Kaina B (1997) rhoB encoding a UV-inducible Ras-related small GTP-binding protein is regulated by GTPases of the Rho family and independent of JNK, ERK, and p38 MAP kinase. J Biol Chem 272:30637–30644

    Article  CAS  PubMed  Google Scholar 

  55. Fritz G, Kaina B, Aktories K (1995) The ras-related small GTP-binding protein RhoB is immediate-early inducible by DNA damaging treatments. J Biol Chem 270:25172–25177

    Article  CAS  PubMed  Google Scholar 

  56. Fritz G, Kaina B (2001) Transcriptional activation of the small GTPase gene rhoB by genotoxic stress is regulated via a CCAAT element. Nucleic Acids Res 29:792–798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jahner D, Hunter T (1991) The ras-related gene rhoB is an immediate-early gene inducible by v-Fps, epidermal growth factor, and platelet-derived growth factor in rat fibroblasts. Mol Cell Biol 11:3682–3690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jiang K, Sun J, Cheng J, Djeu JY, Wei S, Sebti S (2004) Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis. Mol Cell Biol 24:5565–5576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ahn J, Choi JH, Won M, Kang CM, Gyun MR, Park HM, Kim CH, Chung KS (2011) The activation of p38 MAPK primarily contributes to UV-induced RhoB expression by recruiting the c-Jun and p300 to the distal CCAAT box of the RhoB promoter. Biochem Biophys Res Commun 409:211–216

    Article  CAS  PubMed  Google Scholar 

  60. Chung KS et al (2013) A novel antitumor piperazine alkyl compound causes apoptosis by inducing RhoB expression via ROSmediated cAbl/p38 MAPK signaling. Cancer Chemother Pharmacol 72:1315–1324

    Article  CAS  PubMed  Google Scholar 

  61. Delarue FL et al (2007) Farnesyltransferase and geranylgeranyltransferase I inhibitors upregulate RhoB expression by HDAC1 dissociation, HAT association and histone acetylation of the RhoB promoter. Oncogene 26:633–640

    Article  CAS  PubMed  Google Scholar 

  62. Kim BK et al (2014) p300 cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription in NSC126188-mediated apoptosis. Biochim Biophys Acta 1839:364–373

    Article  CAS  PubMed  Google Scholar 

  63. Kim BK et al (2011) Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618. Carcinogenesis 32:254–261

    Article  PubMed  CAS  Google Scholar 

  64. Won KJ et al (2014) NSC126188 induces apoptosis of prostate cancer PC-3 cells through inhibition of Akt membrane translocation, FoxO3a activation, and RhoB transcription. Apoptosis 19:179–190

    Article  CAS  PubMed  Google Scholar 

  65. Kim BK et al (2011) NSC126188, a piperazine alkyl derivative, induces apoptosis via upregulation of RhoB in HeLa cells. Invest New Drugs 29:853–860

    Article  CAS  PubMed  Google Scholar 

  66. Ho HH, Chang CS, Ho WC, Liao SY, Lin WL, Wang CJ (2013) Gallic acid inhibits gastric cancer cells metastasis and invasive growth via increased expression of RhoB, downregulation of AKT/small GTPase signals and inhibition of NF-kappaB activity. Toxicol Appl Pharmacol 266:76–85

    Article  CAS  PubMed  Google Scholar 

  67. Suboj P, Babykutty S, Gopi DRV, Nair RS, Srinivas P, Gopala S (2012) Aloe emodin inhibits colon cancer cell migration/angiogenesis by downregulating MMP-2/9, RhoB and VEGF via reduced DNA binding activity of NF-kappaB. Eur J Pharm Sci 45:581–591

    Article  CAS  PubMed  Google Scholar 

  68. Jiang K, Delarue FL, Sebti SM (2004) EGFR, ErbB2 and Ras but not Src suppress RhoB expression while ectopic expression of RhoB antagonizes oncogene-mediated transformation. Oncogene 23:1136–1145

    Article  CAS  PubMed  Google Scholar 

  69. Yoon YS, Choo JH, Yoo T, Kang K, Chung JH (2007) RhoB is epigenetically regulated in an age-and tissue-specific manner. Biochem Biophys Res Commun 362:164–169

    Article  CAS  PubMed  Google Scholar 

  70. Mokady D, Meiri D (2015) RhoGTPases–a novel link between cytoskeleton organization and cisplatin resistance. Drug Resist Updat 19:22–32

    Article  PubMed  Google Scholar 

  71. Guan X, Chen S, Zhao Y (2018) The role of RhoC in malignant tumor invasion, metastasis and targeted therapy. Histol Histopathol 33(3):255–260

    PubMed  Google Scholar 

  72. Ridley AJ (2013) RhoA, RhoB and RhoC have different roles in cancer cell migration. J Microsc 251:242–249

    Article  CAS  PubMed  Google Scholar 

  73. Lang S, Busch H, Boerries M, Brummer T, Timme S, Lassmann S, Aktories K, Schmidt G (2017) Specific role of RhoC in tumor invasion and metastasis. Oncotarget 8:87364–87378

    PubMed  PubMed Central  Google Scholar 

  74. Xu XD, Shen HB, Zhu L, Lu JQ, Zhang L, Luo ZY, Wu YQ (2017) Anti-RhoC siRNAs inhibit the proliferation and invasiveness of breast cancer cells via modulating the KAI1, MMP9, and CXCR4 expression. Onco Targets Ther 10:1827–1834

    Article  PubMed  PubMed Central  Google Scholar 

  75. Croft DR et al (2011) p53-mediated transcriptional regulation and activation of the actin cytoskeleton regulatory RhoC to LIMK2 signaling pathway promotes cell survival. Cell Res 21:666–682

    Article  CAS  PubMed  Google Scholar 

  76. Bellovin DI, Simpson KJ, Danilov T, Maynard E, Rimm DL, Oettgen P, Mercurio AM (2006) Reciprocal regulation of RhoA and RhoC characterizes the EMT and identifies RhoC as a prognostic marker of colon carcinoma. Oncogene 25:6959–6967

    Article  CAS  PubMed  Google Scholar 

  77. Tian Y, Liu Y, Qu J, Li K, Qin D, Huang A, Tang H (2013) HBV regulated RhoC expression in HepG2.2.15 cells by enhancing its promoter activity. J Basic Microbiol 53:461–468

    Article  CAS  PubMed  Google Scholar 

  78. Qin D, Li K, Qu J, Wang S, Zou C, Sheng Y, Huang A, Tang H (2013) HBx and HBs regulate RhoC expression by upregulating transcription factor Ets-1. Arch Virol 158:1773–1781

    Article  CAS  PubMed  Google Scholar 

  79. Luo J, Li D, Wei D, Wang X, Wang L, Zeng X (2017) RhoA and RhoC are involved in stromal cell-derived factor-1-induced cell migration by regulating F-actin redistribution and assembly. Mol Cell Biochem 436:13–21

    Article  CAS  PubMed  Google Scholar 

  80. Zhou X, Guo X, Chen M, Xie C, Jiang J (2018) HIF-3alpha promotes metastatic phenotypes in pancreatic cancer by transcriptional regulation of the RhoC-ROCK1 signaling pathway. Mol Cancer Res 16:124–134

    Article  CAS  PubMed  Google Scholar 

  81. Egami Y, Kawai K, Araki N (2017) RhoC regulates the actin remodeling required for phagosome formation during FcgammaR-mediated phagocytosis. J Cell Sci 130:4168–4179

    Article  PubMed  CAS  Google Scholar 

  82. Ji H, Tang H, Lin H, Mao J, Gao L, Liu J, Wu T (2014) Rho/Rock cross-talks with transforming growth factor-beta/Smad pathway participates in lung fibroblast-myofibroblast differentiation. Biomed Rep 2:787–792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Manickam N, Patel M, Griendling KK, Gorin Y, Barnes JL (2014) RhoA/Rho kinase mediates TGF-beta1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species. Am J Physiol Renal Physiol 307:F159–F171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Crosas-Molist E, Bertran E, Rodriguez-Hernandez I, Herraiz C, Cantelli G, Fabra A, Sanz-Moreno V, Fabregat I (2017) The NADPH oxidase NOX4 represses epithelial to amoeboid transition and efficient tumour dissemination. Oncogene 36:3002–3014

    Article  CAS  PubMed  Google Scholar 

  85. Bravo-Nuevo A, O’Donnell R, Rosendahl A, Chung JH, Benjamin LE, Odaka C (2011) RhoB deficiency in thymic medullary epithelium leads to early thymic atrophy. Int Immunol 23:593–600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ungefroren H, Witte D, Lehnert H (2018) The role of small GTPases of the Rho/Rac family in TGF-beta-induced EMT and cell motility in cancer. Dev Dyn 247:451–461

    Article  CAS  PubMed  Google Scholar 

  87. Menezes ME, Shen XN, Das SK, Emdad L, Sarkar D, Fisher PB (2016) MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor beta1 to enhance epithelial–mesenchymal transition in breast cancer. Oncotarget 7:80175–80189

    Article  PubMed  PubMed Central  Google Scholar 

  88. Nomikou E, Stournaras C, Kardassis D (2017) Functional analysis of the promoters of the small GTPases RhoA and RhoB in embryonic stem cells. Biochem Biophys Res Commun 491:754–759

    Article  CAS  PubMed  Google Scholar 

  89. Ho TT, Merajver SD, Lapiere CM, Nusgens BV, Deroanne CF (2008) RhoA-GDP regulates RhoB protein stability potential involvement of RhoGDIalpha. J Biol Chem 283:21588–21598

    Article  CAS  PubMed  Google Scholar 

  90. Vega FM, Fruhwirth G, Ng T, Ridley AJ (2011) RhoA and RhoC have distinct roles in migration and invasion by acting through different targets. J Cell Biol 193:655–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  93. Mizoguchi F, Murakami Y, Saito T, Miyasaka N, Kohsaka H (2013) miR-31 controls osteoclast formation and bone resorption by targeting RhoA. Arthritis Res Ther 15:R102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Huang B, Luo W, Sun L, Zhang Q, Jiang L, Chang J, Qiu X, Wang E (2013) MiRNA-125a-3p is a negative regulator of the RhoA-actomyosin pathway in A549 cells. Int J Oncol 42:1734–1742

    Article  CAS  PubMed  Google Scholar 

  95. Care A et al (2007) MicroRNA-133 controls cardiac hypertrophy. Nat Med 13:613–618

    Article  CAS  PubMed  Google Scholar 

  96. Chiba Y, Tanabe M, Goto K, Sakai H, Misawa M (2009) Down-regulation of miR-133a contributes to up-regulation of Rhoa in bronchial smooth muscle cells. Am J Respir Crit Care Med 180:713–719

    Article  CAS  PubMed  Google Scholar 

  97. Ding J et al (2010) Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA. Nat Cell Biol 12:390–399

    Article  CAS  PubMed  Google Scholar 

  98. Kong W, Yang H, He L, Zhao JJ, Coppola D, Dalton WS, Cheng JQ (2008) MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 28:6773–6784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sabatel C et al (2011) MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells. PLoS One 6:e16979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Connolly EC, Van Doorslaer K, Rogler LE, Rogler CE (2010) Overexpression of miR-21 promotes an in vitro metastatic phenotype by targeting the tumor suppressor RHOB. Mol Cancer Res 8:691–700

    Article  CAS  PubMed  Google Scholar 

  101. Liu M, Tang Q, Qiu M, Lang N, Li M, Zheng Y, Bi F (2011) miR-21 targets the tumor suppressor RhoB and regulates proliferation, invasion and apoptosis in colorectal cancer cells. FEBS Lett 585:2998–3005

    Article  CAS  PubMed  Google Scholar 

  102. Glorian V, Maillot G, Poles S, Iacovoni JS, Favre G, Vagner S (2011) HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis. Cell Death Differ 18:1692–1701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Jiang L, Liu X, Kolokythas A, Yu J, Wang A, Heidbreder CE, Shi F, Zhou X (2010) Downregulation of the Rho GTPase signaling pathway is involved in the microRNA-138-mediated inhibition of cell migration and invasion in tongue squamous cell carcinoma. Int J Cancer 127:505–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Islam M, Datta J, Lang JC, Teknos TN (2014) Down regulation of RhoC by microRNA-138 results in de-activation of FAK, Src and Erk1/2 signaling pathway in head and neck squamous cell carcinoma. Oral Oncol 50:448–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Liu BL, Sun KX, Zong ZH, Chen S, Zhao Y (2016) MicroRNA-372 inhibits endometrial carcinoma development by targeting the expression of the Ras homolog gene family member C (RhoC). Oncotarget 7:6649–6664

    PubMed  Google Scholar 

  106. Myers C, Charboneau A, Cheung I, Hanks D, Boudreau N (2002) Sustained expression of homeobox D10 inhibits angiogenesis. Am J Pathol 161:2099–2109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ma L, Teruya-Feldstein J, Weinberg RA (2007) Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449:682–688

    Article  CAS  PubMed  Google Scholar 

  108. Knirsh R, Ben-Dror I, Modai S, Shomron N, Vardimon L (2016) MicroRNA 10b promotes abnormal expression of the proto-oncogene c-Jun in metastatic breast cancer cells. Oncotarget 7:59932–59944

    Article  PubMed  PubMed Central  Google Scholar 

  109. Wang YF, Li Z, Zhao XH, Zuo XM, Zhang Y, Xiao YH, Li J, Peng ZH (2015) MicroRNA-10b is upregulated and has an invasive role in colorectal cancer through enhanced Rhoc expression. Oncol Rep 33:1275–1283

    Article  CAS  PubMed  Google Scholar 

  110. Sasayama T, Nishihara M, Kondoh T, Hosoda K, Kohmura E (2009) MicroRNA-10b is overexpressed in malignant glioma and associated with tumor invasive factors, uPAR and RhoC. Int J Cancer 125:1407–1413

    Article  CAS  PubMed  Google Scholar 

  111. Wu DD, Chen X, Sun KX, Wang LL, Chen S, Zhao Y (2017) Role of the lncRNA ABHD11-AS1 in the tumorigenesis and progression of epithelial ovarian cancer through targeted regulation of RhoC. Mol Cancer 16:138

    Article  PubMed  PubMed Central  Google Scholar 

  112. Sang XB, Zong ZH, Wang LL, Wu DD, Chen S, Liu BL, Zhao Y (2017) E2F-1 targets miR-519d to regulate the expression of the ras homolog gene family member C. Oncotarget 8:14777–14793

    Article  PubMed  PubMed Central  Google Scholar 

  113. Zhou W, Zhang C, Jiang H, Zhang Z, Xie L, He X (2015) MiR-493 suppresses the proliferation and invasion of gastric cancer cells by targeting RhoC. Iran J Basic Med Sci 18:1027–1033

    PubMed  PubMed Central  Google Scholar 

  114. Yau WL et al (2013) Over-expression of miR-106b promotes cell migration and metastasis in hepatocellular carcinoma by activating epithelial–mesenchymal transition process. PLoS One 8:e57882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Chen S, Chen X, Xiu YL, Sun KX, Zhao Y (2015) Inhibition of ovarian epithelial carcinoma tumorigenesis and progression by microRNA 106b mediated through the RhoC pathway. PLoS One 10:e0125714

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Liu Y, Song N, Ren K, Meng S, Xie Y, Long Q, Chen X, Zhao X (2013) Expression loss and revivification of RhoB gene in ovary carcinoma carcinogenesis and development. PLoS One 8:e78417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by a Grant from the Hellenic Ministry for Education, Research and Religious Affairs (THALIS MIS 380334) to DK and CS. EN and ML were supported by a doctoral fellowship from IKY-Siemens Research Grants.

Author information

Authors and Affiliations

  1. Laboratory of Biochemistry, Department of Medicine, University of Crete, 71003, Heraklion, Greece

    Eirini Nomikou, Melina Livitsanou, Christos Stournaras & Dimitris Kardassis

  2. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 71110, Heraklion, Greece

    Dimitris Kardassis

Authors
  1. Eirini Nomikou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melina Livitsanou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christos Stournaras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dimitris Kardassis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dimitris Kardassis.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nomikou, E., Livitsanou, M., Stournaras, C. et al. Transcriptional and post-transcriptional regulation of the genes encoding the small GTPases RhoA, RhoB, and RhoC: implications for the pathogenesis of human diseases. Cell. Mol. Life Sci. 75, 2111–2124 (2018). https://doi.org/10.1007/s00018-018-2787-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2787-y

Keywords

Search

Navigation