|Written||2007-02||Nora C Heisterkamp|
|Division of Hematology-Oncology, Children's Hospital of Los Angeles, CA, USA|
|Updated||2012-04||Nora C Heisterkamp|
|Division of Hematology-Oncology, Children's Hospital of Los Angeles, CA, USA|
(Note : for Links provided by Atlas : click)
|Location||17q25.3 [Link to chromosome band 17q25]|
|Location_base_pair||Starts at 82031656 and ends at 82034204 bp from pter ( according to hg19-Feb_2009) [Mapping RAC3.png]|
|Local_order||Located telomeric to the BROV region. Centromeric to LRRC45 - Rac3 - DCXR telomeric.|
|Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)|
|RAC3 (17q25.3) / ABCA8 (17q24.2)|
|Note||With 5\271 end towards the centromere. Nucleotide 203731-2061912 of contig NT_010663.|
|Note||6 exons, spread out over approximately 2,4 kb.|
|Description||The Rac3 gene encompasses 6 exons on chromosome 17. Exon 1 encodes residues 1-12, exon 2 residues 13-36, exon 3 residues 37-75, exon 4 residues 76-96, exon 5 residues 97-149 and exon 6 residues 150-192.|
|Transcription||Human Rac3 mRNA is a single species of around 1 kb. No splice variants have been reported. Factors that would regulate gene expression on a transcriptional level have not yet been reported.|
|Pseudogene||No pseudogenes of Rac3 are reported in human.|
|Note||The Rac3 gene encodes a single protein of 192 amino acid residues.|
|Schematic representation of the Rac3 protein (not to scale). Mutations that generate mutants that are locked in a certain conformation - constitutively active or dominant negative - are shown. The C-terminal end contains the CTVM motif that is post-translationally modified the three last amino acid residues are removed and the C residue is geranyl-geranylated.|
|Description||Rac3 is a small 21 kDa GTPase that acts as a molecular switch. In its active form, it is bound to GTP, whereas it is inactive in its GDP-bound form. Racs are controlled by guanidine activating proteins (GEFs) that exchange bound GDP for GTP and by GTPase activating proteins (GAPs) that promote GTP hydrolysis. Because of the hydrophobic isoprenyl moiety at the C-terminal end, it is associated with membranes. In the cytoplasm it associates with the chaperone RhoGDI.|
|Expression||Rac3 mRNA was reported in human cell lines including GM04155 (lymphoblastic leukemia), K562 (CML), 5838 (Ewing sarcoma), HL60 (promyelocytic leukemia) and DU4475 (breast cancer). Rac3 expression was reported using semi-quantitative RT/PCR in gastric tumor and adjacent normal tissue as well as gastric cancer cell lines. Expression of Rac3 using RT/PCR (38 cycles) was reported in human brain, liver, kidney and pancreas poly A RNA and also 19% of brain tumors expressed Rac3 mRNA. Rac3-specific polyclonal antibodies were used to show Rac3 protein in the brain (deep cerebellar nuclei and the pons) in 7 day old mice. Low level expression of mouse rac3 has been reported in bone-marrow-derived monocytes and in B-lineage lymphoblasts using standard and Real-Time RT/PCR. Expression of Rac3 is inferred because of the effect of siRNA knockdown in cell lines including HCT116 colon cancer, MDA-MB231 breast cancer, HeLa, and PC3 prostate cancer (Zhu et al., 2011). Real-time RT/PCR showed Rac3 mRNA in prostate cancer biopsy samples (Engers et al., 2007). Analysis of gene expression profiling datasets (Chang et al., 2005) in breast cancer samples showed Rac3 expression (Walker et al., 2011).|
|Localisation||The Rac3 protein is located on endomembranes and cell membranes. Nuclear localization was also reported (Walker et al., 2011).|
|Function||Rac proteins regulate a variety of functions including cytoskeletal organization, cell cycle, reactive oxygen species production, and vesicle trafficking. In its activity on reactive oxygen species production, Rac3 is able to activate Nox1, Nox2 and Nox3 (Miyano et al., 2009; Miyano and Sumimoto, 2012). Studies of null mutant Rac3 mice showed that Rac3 regulates cerebellar functions and in a mouse model plays a role in leukemia development caused by the Bcr/Abl oncogene. Point mutations (N26D, F37L, Y40C, N43D) were introduced into different critical residues of the effector domain of Rac3 and the effects of these were investigated on the ability of Rac3 to regulate membrane ruffles, c-jun activation and transformation. Transformation was assayed as the ability to cooperate with activated Raf in focus formation of NIH3T3 cells and the ability to promote growth of these cells in soft agar. Rac3 was found to negatively regulate autophagy in colon, breast and prostate cancer cell lines, since its knockdown stimulated LC3-II expression (Zhu et al., 2011). Different effects on migration are reported. Rac3 negatively regulates diapedesis of PC3 cells, since knockdown using siRNA increases migration of PC3 prostate cancer cells through a BMEC layer (Chatterjee et al., 2011). In contrast, overexpression of Rac3 in MCF7 breast cancer cells stimulates E2-induced migration (Walker et al., 2011).|
|Homology||Rac3 is most closely related to Rac1 and Rac2. On a nucleotide level human Rac3 has 77% identity with Rac1, 83% identity with Rac2 and 69% identity with RhoG. On an amino acid level, Rac3 and Rac1 differ in 14/192 residues (92% identical), whereas Rac3 and Rac2 differ in 22/192 residues (89% identical). Rac belongs to the extended Rho family of small G-proteins. Biochemically, Rac1 and Rac3 are closely related and have overlapping (Corbetta et al., 2009; Pennucci et al., 2011; Basso et al., 2011) as well as distinct functions. Rac3 differs from Rac1 in the presence of a residue in its C-terminal end, S151, which is A151 in Rac1 and mediates binding of Rac3 to ERα (Walker et al., 2011). Rac3 and Rac1 also differ in their effect on NIE-115 neuroblastoma cells, in which Rac3 induces cell rounding and Rac1 induces spreading (Hajdo-Milasinovic et al., 2007; Hajdo-Milasinovic et al., 2009).|
4. Implicated in
|Note|| Using in situ hybridization, Rac3 was reported to lies outside of the BROV region commonly deleted in breast and ovarian cancer. |
Activated Rac3 protein was reported in MDA-435, T47D and MCF7 breast cancer cell lines and 1 of 3 patient samples using a GST-Pak pull-down assay to detect activated Rac.
siRNA against Rac3 inhibits SNB19 glioblastoma and BT549 breast cancer cell line invasion in an in vitro assay.
It was showed that introduction of a constitutively active Rac3 into the MDA-MB-435 breast cancer cell line caused increased invasion and motility in vitro.
Transgenic mice with tissue specific expression of constitutively active (V12)Rac3 in the mammary gland were generated. Post-lactational female mice had delayed involution.
In the MCF7 breast cancer cell line, E2-stimulated migration was decreased by siRNA-mediated knockdown of Rac3, and Rac3 interacted with the ERα in a ligand-dependent manner (Chatterjee et al., 2011). Meta-analysis of gene expression profiling datasets of breast cancer samples (Chang et al., 2005) for Rac3 showed that expression levels correlated with increased probability of metastatic events (Walker et al., 2011).
|Note||Semi-quantitative RT/PCR was used to examine Rac3 mRNA expression in gastric cancer tissues and 7 gastric cell lines. Rac3 expression was detected in the tumor samples but there was no statistically significant difference between the expression levels in gastric cancer and adjacent non-tumorous tissues. The cell lines had a varying but detectable Rac3 expression.|
|Note||RT-PCR was used to evaluate Rac3 mRNA expression in human brain tumor tissues. Expression of rac3 was reported in 3/9 meningiomas, 1/11 astrocytomas, 1/6 pituitary adenomas. The PCR fragments were subcloned and sequenced, and mutations were reported in Rac3 in 12/19 brain tumors including E10V, V14E, D35N, P35S, N43D, V46A, D57V, R57P, L67V, S83F, V85A, E100G, H104L, P109H, R120H, T125P, S158P, P180T, V182E, V182A, H184L and G186E.|
|Note||Using real-time RT/PCR, increased Rac3 mRNA was detected in involved prostate cancer biopsy samples compared to adjacent normal tissue (Engers et al., 2007).|
5. To be noted
| There is a second gene that is named RAC3 in some publications. This protein is functionally and structurally unrelated to the small GTPase Rac3. This is the steroid receptor coactivator-3, or nuclear receptor coactivator SRC-3/AIB1/ACTR/pCIP/RAC3/TRAM-1.|
Probes 1-12 from NM_005052-links-probes
1: ProbeID:6597734 TaqMan gene expression (TaqMan) probe Hs00414037_g1 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for real time qRT-PCR gene expression profiling. Reagent is available from Applied Biosystems.
2: ProbeID:3104502 Small interfering RNA (siRNA) probe for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Has been used for RNA interference (RNAi). Reference Chan et al., 2005
3: ProbeID:3104501 Small interfering RNA (siRNA) probe for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Has been used for RNA interference (RNAi). Reference Chan et al., 2005
4: ProbeID:1163472 Resequencing amplicon (RSA) probe RSA001057586 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery.
5: ProbeID:1163461 Resequencing amplicon (RSA) probe RSA001057592 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery.
6: ProbeID:1157480 Resequencing amplicon (RSA) probe RSA001229136 for Homo sapiens genes ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3) and leucine rich repeat containing 45 (LRRC45). Developed for SNP discovery.
7. ProbeID:1152860 Resequencing amplicon (RSA) probe RSA001400685 for Homo sapiens genes ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3) and leucine rich repeat containing 45 (LRRC45). Developed for SNP discovery.
8: ProbeID:1152824 Resequencing amplicon (RSA) probe RSA001401207 for Homo sapiens genes ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3) and leucine rich repeat containing 45 (LRRC45). Developed for SNP discovery.
9: ProbeID:1151274 Resequencing amplicon (RSA) probe RSA001457703 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery.
10: ProbeID:1151272 Resequencing amplicon (RSA) probe RSA001457859 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery.
11: ProbeID:1151270 Resequencing amplicon (RSA) probe RSA001458006 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery.
12: ProbeID:1151269 Resequencing amplicon (RSA) probe RSA001458005 for Homo sapiens gene ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) (RAC3). Developed for SNP discovery.
13. Chan et al. (2005) reported TaqMan primers useful in quantifying human Rac3 expression.
14. Pan et al. (2004) reported primers for semi-quantitative RT/PCR for human Rac3 that yielded a 249 bp
15. Hwang et al. (2005) reported primers for RT-PCR of human RNA. Fw primer was 5'-AATTCATGCAGGCCATCAAGT-3' and the reverse primer 5'-CTAGAAGACGGTGCACTT-3'.
|Absence of Rac1 and Rac3 GTPases in the nervous system hinders thymic, splenic and immune-competence development.|
|Basso V, Corbetta S, Gualdoni S, Tonoli D, Poliani PL, Sanvito F, Doglioni C, Mondino A, de Curtis I.|
|Eur J Immunol. 2011 May;41(5):1410-9. doi: 10.1002/eji.201040892. Epub 2011 Apr 15.|
|Rac1 and Rac3 isoform activation is involved in the invasive and metastatic phenotype of human breast cancer cells.|
|Baugher PJ, Krishnamoorthy L, Price JE, Dharmawardhane SF.|
|Breast Cancer Res. 2005;7(6):R965-74. Epub 2005 Sep 30.|
|Differential distribution of Rac1 and Rac3 GTPases in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiation.|
|Bolis A, Corbetta S, Cioce A, de Curtis I.|
|Eur J Neurosci. 2003 Nov;18(9):2417-24.|
|Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion.|
|Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR, Symons M.|
|Oncogene. 2005 Nov 24;24(53):7821-9.|
|Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival.|
|Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T, Dai H, He YD, van't Veer LJ, Bartelink H, van de Rijn M, Brown PO, van de Vijver MJ.|
|Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3738-43. Epub 2005 Feb 8.|
|Individual rac GTPases mediate aspects of prostate cancer cell and bone marrow endothelial cell interactions.|
|Chatterjee M, Sequeira L, Jenkins-Kabaila M, Dubyk CW, Pathak S, van Golen KL.|
|J Signal Transduct. 2011;2011:541851. Epub 2011 Jun 27.|
|Generation of rac3 null mutant mice: role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia.|
|Cho YJ, Zhang B, Kaartinen V, Haataja L, de Curtis I, Groffen J, Heisterkamp N.|
|Mol Cell Biol. 2005 Jul;25(13):5777-85.|
|Essential role of Rac1 and Rac3 GTPases in neuronal development.|
|Corbetta S, Gualdoni S, Ciceri G, Monari M, Zuccaro E, Tybulewicz VL, de Curtis I.|
|FASEB J. 2009 May;23(5):1347-57. Epub 2009 Jan 6.|
|Structure and chromosomal assignment to 22q12 and 17qter of the ras-related Rac2 and Rac3 human genes.|
|Courjal F, Chuchana P, Theillet C, Fort P.|
|Genomics. 1997 Sep 1;44(2):242-6.|
|Prognostic relevance of increased Rac GTPase expression in prostate carcinomas.|
|Engers R, Ziegler S, Mueller M, Walter A, Willers R, Gabbert HE.|
|Endocr Relat Cancer. 2007 Jun;14(2):245-56.|
|Characterization of RAC3, a novel member of the Rho family.|
|Haataja L, Groffen J, Heisterkamp N.|
|J Biol Chem. 1997 Aug 15;272(33):20384-8.|
|Comparative functional analysis of the Rac GTPases.|
|Haeusler LC, Blumenstein L, Stege P, Dvorsky R, Ahmadian MR.|
|FEBS Lett. 2003 Dec 18;555(3):556-60.|
|Rac3 inhibits adhesion and differentiation of neuronal cells by modifying GIT1 downstream signaling.|
|Hajdo-Milasinovic A, van der Kammen RA, Moneva Z, Collard JG.|
|J Cell Sci. 2009 Jun 15;122(Pt 12):2127-36.|
|Expression of Rac3 in human brain tumors.|
|Hwang SL, Chang JH, Cheng TS, Sy WD, Lieu AS, Lin CL, Lee KS, Howng SL, Hong YR.|
|J Clin Neurosci. 2005 Jun;12(5):571-4.|
|Rac3-mediated transformation requires multiple effector pathways.|
|Keller PJ, Gable CM, Wing MR, Cox AD.|
|Cancer Res. 2005 Nov 1;65(21):9883-90.|
|Targeted expression of activated Rac3 in mammary epithelium leads to defective postlactational involution and benign mammary gland lesions.|
|Leung K, Nagy A, Gonzalez-Gomez I, Groffen J, Heisterkamp N, Kaartinen V.|
|Cells Tissues Organs. 2003;175(2):72-83.|
|The insert region of the Rac GTPases is dispensable for activation of superoxide-producing NADPH oxidases.|
|Miyano K, Koga H, Minakami R, Sumimoto H.|
|Biochem J. 2009 Aug 13;422(2):373-82.|
|Assessment of the role for Rho family GTPases in NADPH oxidase activation.|
|Miyano K, Sumimoto H.|
|Methods Mol Biol. 2012;827:195-212.|
|The small GTPase RAC3 gene is located within chromosome band 17q25.3 outside and telomeric of a region commonly deleted in breast and ovarian tumours.|
|Morris CM, Haataja L, McDonald M, Gough S, Markie D, Groffen J, Heisterkamp N.|
|Cytogenet Cell Genet. 2000;89(1-2):18-23.|
|Expression of seven main Rho family members in gastric carcinoma.|
|Pan Y, Bi F, Liu N, Xue Y, Yao X, Zheng Y, Fan D.|
|Biochem Biophys Res Commun. 2004 Mar 12;315(3):686-91.|
|Rac1 and Rac3 GTPases regulate the development of hilar mossy cells by affecting the migration of their precursors to the hilus.|
|Pennucci R, Tavano S, Tonoli D, Gualdoni S, de Curtis I.|
|PLoS One. 2011;6(9):e24819. Epub 2011 Sep 20.|
|RAC3 is a pro-migratory co-activator of ER?.|
|Walker MP, Zhang M, Le TP, Wu P, Laine M, Greene GL.|
|Oncogene. 2011 Apr 28;30(17):1984-94. Epub 2011 Jan 10.|
|A role for Rac3 GTPase in the regulation of autophagy.|
|Zhu WL, Hossain MS, Guo DY, Liu S, Tong H, Khakpoor A, Casey PJ, Wang M.|
|J Biol Chem. 2011 Oct 7;286(40):35291-8. Epub 2011 Aug 18.|
|This paper should be referenced as such :|
|RAC3 (ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3))|
|Atlas Genet Cytogenet Oncol Haematol. 2012;16(9):665-668.|
|Free journal version : [ pdf ] [ DOI ]|
|On line version : http://atlasgeneticsoncology.usal.es/classic/Genes/RAC3ID42022ch17q25.html|
|History of this paper:|
|Heisterkamp, NC. RAC3 (ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3)). Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):209-212.|
|Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]|
8. External links
|REVIEW articles||automatic search in PubMed|
|Last year publications||automatic search in PubMed|
|© Atlas of Genetics and Cytogenetics in Oncology and Haematology||indexed on : Thu Jan 17 19:06:11 CET 2019|
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