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RNASET2 (ribonuclease T2)

Identity

Other namesRNASE6PL
RP11-514O12.3
bA514O12.3
HGNC (Hugo) RNASET2
LocusID (NCBI) 8635
Location 6q27
Location_base_pair Starts at 167343004 and ends at 167370077 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Telomeric to RPS6KA2, centromeric to FGFR1OP.
 
Note This gene represents the first human member of the Rh/T2/S-glycoprotein family of extracellular ribonucleases. It belongs to the recently defined class of tumor-antagonizing genes, based on its ability to suppress tumor growth in vivo, but not in vitro. It is likely involved in the pathogenesis of several human neoplasias (both solid and haematological) such as ovarian cancer, melanoma and non-Hodgkin lymphoma.
Mutations in this gene have also been recently described in children affected by a rare congenital neurological defect. Moreover, GWAS studies have recently reported the association of gene variants mapping close to the RNASET2 gene with susceptibilty to a few autoimmune disorders.

DNA/RNA

 
  I-IX: RNASET2 exons; Red boxes: CAS I and CAS II catalytic sites; Dark green boxes: untranslated regions.
Description The RNASET2 gene has been mapped in the peritelomeric region of the long arm of human chromosome 6 (6q27), which has been consistently reported to be rearreanged in several human neoplasias. It's coding region is split in 9 exons, spanning approximatly 27 kb of genomic DNA. The translation initiation codon is located in exon 1 and the stop codon in exon 9. Exons III and VI encode the two CAS motifs (Catalytic Active Sites) responsible for the ribonuclease activity of the RNASET2 protein. However, the catalytic activity of the RNASET2 protein is apparently not required for some biological functions, as described for other members of the T2-Rh-S RNase gene family.
Transcription The RNASET2 gene is transcribed in the telomere-to-centromere orientation to produce an ubiquitously expressed mRNA approximately 1,4 kb in length. EST clones representing splice variants of the same gene have been described. Transcription of this gene is rather ubiquitous, with highest expression levels being reported in spleen, pancreas and leukocytes.
Pseudogene A processed pseudogene showing 85% identity with RNASET2 mRNA maps to chromosome 7p11.2. The expression pattern of this pseudogene is not known.

Protein

 
  The RNASET2 protein contains 256 aminoacids. Gold box: signal peptide for secretion (residues 1-24); Gray box: catalytic fold; Red boxes: Conserved Active Sites (CAS I-II); Yellow boxes: putative N-glycosilation sites.
Description The aminoacid sequence of RNASET2 depicts a typical member of the highly conserved Rh7T2/S family of extracellular, acid ribonucleases. The X-ray structure of the protein was recently reported, showing the occurrence of the α+β core fold typically observed in other members of the Rh/T2/S protein family. The catalytic activity of the protein was shown to be significantly inhibited by zinc and copper ions.
Expression In normal human tissues, the RNASET2 protein has been detected in pancreas, stomach, small intestine, colon, salivary glands, liver, thyroid, adrenal glands, lymphoid organs, lungs, melanocytes, ovarian surface and Fallopian tube epithelium. Expression of the RNASET2 protein has also been detected in several human ovarian cancer cell lines and in some melanoma, prostate, pancreatic and breast carcinoma cell lines.
Localisation The full-length RNASET2 protein contains 256 aminoacids and displays an apparent MW of 36 kDa in its secreted form. Two 31 and 27 kDa C-terminal proteolytic products have also been observed intracellularly in several human cancer cell lines. The extracellular RNASET2 protein is detected in cell culture supernatants as the full lenght 36 kDa forms. The intracellular localization pattern of the RNASET2 protein suggests a localization in the secretory compartments (endoplasmic reticulum and Golgi apparatus) but also in lysosomes and processing bodies (P-bodies).
Function Biochemical function: RNASET2 is an acid ribonuclease with optimal activity at pH 5 and preferential cleavage of poly-A and poly-U homo-polyribonucleotides.
Biological function: RNASET2 behaves as a tumor antagonizing gene in ovarian cancer models, since experimental manipulation of this gene's expression levels in human ovarian cancer cell lines is associated with a significant change in their tumorigenic and metastasizing potential in vivo. The oncosuppressive role of this protein in ovarian cancer models is associated with a marked recruitment of cells form the monocyte/macrophage lineage within the tumor mass. In an experimental model of colorectal cancer, recombinant RNASET2 was also found to display a marked oncosuppressive activity. Strikingly, in both models the ribonuclease catalytic activity was apparently dispensable for RNASET2 to play such antioncogenic role. A role for in vivo tumor suppression for RNASET2 has also been established in a model of malignant melanoma.
Moreover, the human RNASET2 gene has been recently implicated in sperm motility and stress-induced apoptosis in melanocytes.
Recent investigations carried out on RNASET2 orthologs have suggested several additional biological roles for this gene family, such as in vivo priming of dendritic cells for Th2-helper response, inhibition of angiogenesis in vivo, ribosomal RNA decay in plants and CNS physiology.
Homology The primary sequenze of RNASET2 shows strong homology to the Rh/T2/S family of secreted ribonucleases.

Mutations

Note Epigenetics: The RNASET2 gene has been reported to be frequently down-regulated in several human ovarian cancer cell lines and primary tumors. The underlying molecular mechanism is currently unknown.
Germinal A common exon-9 missense C708T germline mutation has been described but no evidence for an association of this allele with human cancer was found.
A missense mutation (550T>C ; C184R) and a 2,5 kb deletion spanning exon 2 were found to segregate in families affected with cystic leukoencephalopathy.
Somatic A few common polymorphisms in exons 1, 8 and 9 have been described. In general, coding mutations are rarely found in tumor samples.

Implicated in

Entity Ovarian cancer
Note Loss of expression or downregulation of RNASET2 occurs in a significant fraction of human ovarian cancer cell lines and primary ovarian tumours. Moreover, the genomic region (chromosome 6q27) where the RNASET2 genes maps has been reported to be frequently deleted or otherwise rearranged in a high fraction of ovarian cancer samples. However, no mutation in the RNASET2 gene have been described so far in human ovarian cancer samples. Therefore, this gene seems to be involved in tumor suppression mainly by means of its downregulation at the transcript/protein level in this cancer type. When overexpressed by gene transfer experiments in human ovarian cancer cell lines displaying a low level of endogenous mRNA, RNASET2 strongly suppresses the tumorigenic and metastatic potential of these cell lines in a murine xenogratf model in vivo. The same observation was reported following a complementary experiment, i.e. by knocking-down RNASET2 expression in a poorly aggressive ovarian cancer cell line expressing high levels of endogenous RNASET2.
In both in vivo models, RNASET2-mediated tumor suppression was associated with a marked recruitment of cells from the monocyte/macrophage lineage in the tumor mass. Further experiments have demonstrated a direct chemotactic role for cells from the monocyte/macrophage carried out by the RNASET2 protein. Very recently, downregulation of RNASET2 expression has been associated with resistance to cis-platin and carboplatin in ovarian cancer cells and tissues.
  
Entity Malignant melanoma
Note Besides ovarian carcinoma, the chromosome region 6q27 (where the RNASET2 genes maps) has been reported to be frequently deleted or rearranged in malignant melanoma. Downregulation of RNASET2 has also been reported in cell lines representing this cancer type. Overexpression of RNASET2 in the human melanoma-derived SK-MEL28 cell line was associated with a significant suppression of tumor growth in vivo (in a xenograft model with immunocompromised mice), but not in vitro, supporting the notion of RNASET2 as a tumor-antagonizing gene whose oncosuppressive action is carried out asimmetrically, i.e. only in the context of a complex tissue architecture where a significant cross-talk between cancer cells and the stromal compartment take place. Moreover, the T2 RNase protein encoded from the Aspergillus niger ortholog gene has been shown to inhibit human melanoma cell growth and metastasis in a xenograft model. The underlying oncosuppressive mechanism in this model was the inhibition of tumor angiogenesis by means of competitive inhibition with angiogenin.
  
Entity Colorectal cancer
Note In an HT29 human colon cancer-derived xenograft experimental model, human recombinant RNASET2 was shown to greatly suppress tumor growth in vivo independent from its catalytic activity. Tumor angiogenesis was mainly affected by recombinant RNASET2 injection in this cancer model.
  
Entity Anaplastic large cell lymphoma
Note More recently, screening of a protein microarray with sera from anaplastic large cell lymphoma (ALCL) patients identified RNASET2 as an ALK-negative ALCL-associated antigen.
  
Entity Cystic leukoencephalopathy
Disease Several loss-of function mutations have been reported in probands affected by cystic leukoencephalopathy, an autosomal recessive disorder whose clinical and radiological phenotype is indistinguishable with respect to the pattern of brain abnormalities observed in people suffering from congenital cytomegalovirus infection. Affected people develop several neurologic abnormalities in the early post-natal period, including psychomotor defects, seizures and sensorineural hearing impairment, characterized by a diagnostic MRI pattern.
Cytogenetics Six independent mutations in the RNASET2 gene have been reported in both familial and sporadic cases affected by cystic leukoencephalopathy. All mutations are predicted to result in a loss of function phenotype.
Abnormal Protein The C184R mutant RNASET2 protein expressed from the 550T>C allele showed defective intracellular trafficking, likely due to impaired protein folding or stability.
  
Entity Autoimmune disorders
Disease Genome-wide association studies have recently implicated the RNASET2 locus in the susceptibility for a few autoimmune disorder, such as vitiligo, Crohns' disease and Graves' disease.
  

External links

Nomenclature
HGNC (Hugo)RNASET2   21686
Cards
AtlasRNASET2ID518ch6q27
Entrez_Gene (NCBI)RNASET2  8635  ribonuclease T2
GeneCards (Weizmann)RNASET2
Ensembl (Hinxton)ENSG00000026297 [Gene_View]  chr6:167343004-167370077 [Contig_View]  RNASET2 [Vega]
ICGC DataPortalENSG00000026297
AceView (NCBI)RNASET2
Genatlas (Paris)RNASET2
WikiGenes8635
SOURCE (Princeton)NM_003730
Genomic and cartography
GoldenPath (UCSC)RNASET2  -  6q27   chr6:167343004-167370077 -  6q27   [Description]    (hg19-Feb_2009)
EnsemblRNASET2 - 6q27 [CytoView]
Mapping of homologs : NCBIRNASET2 [Mapview]
OMIM612944   612951   
Gene and transcription
Genbank (Entrez)AJ419865 AJ419866 AJ419867 AK001769 AK124363
RefSeq transcript (Entrez)NM_003730
RefSeq genomic (Entrez)AC_000138 NC_000006 NC_018917 NG_016280 NT_025741 NW_001838993 NW_004929328
Consensus coding sequences : CCDS (NCBI)RNASET2
Cluster EST : UnigeneHs.529989 [ NCBI ]
CGAP (NCI)Hs.529989
Alternative Splicing : Fast-db (Paris)GSHG0027066
Alternative Splicing GalleryENSG00000026297
Gene ExpressionRNASET2 [ NCBI-GEO ]     RNASET2 [ SEEK ]   RNASET2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO00584 (Uniprot)
NextProtO00584  [Medical]
With graphics : InterProO00584
Splice isoforms : SwissVarO00584 (Swissvar)
Catalytic activity : Enzyme3.1.27.- [ Enzyme-Expasy ]   3.1.27.-3.1.27.- [ IntEnz-EBI ]   3.1.27.- [ BRENDA ]   3.1.27.- [ KEGG ]   
Domaine pattern : Prosite (Expaxy)RNASE_T2_1 (PS00530)    RNASE_T2_2 (PS00531)   
Domains : Interpro (EBI)RNase_T2-like    RNase_T2_AS   
Related proteins : CluSTrO00584
Domain families : Pfam (Sanger)Ribonuclease_T2 (PF00445)   
Domain families : Pfam (NCBI)pfam00445   
DMDM Disease mutations8635
Blocks (Seattle)O00584
PDB (SRS)3T0O   
PDB (PDBSum)3T0O   
PDB (IMB)3T0O   
PDB (RSDB)3T0O   
Human Protein AtlasENSG00000026297
Peptide AtlasO00584
HPRD10197
IPIIPI00414896   IPI00152444   IPI00939604   IPI00975923   IPI00152442   IPI00967269   IPI00964721   
Protein Interaction databases
DIP (DOE-UCLA)O00584
IntAct (EBI)O00584
FunCoupENSG00000026297
BioGRIDRNASET2
IntegromeDBRNASET2
STRING (EMBL)RNASET2
Ontologies - Pathways
QuickGOO00584
Ontology : AmiGORNA binding  ribonuclease activity  extracellular region  extracellular space  lysosome  endoplasmic reticulum lumen  RNA catabolic process  ribonuclease T2 activity  lysosomal lumen  extracellular vesicular exosome  RNA phosphodiester bond hydrolysis  RNA phosphodiester bond hydrolysis  RNA phosphodiester bond hydrolysis, endonucleolytic  
Ontology : EGO-EBIRNA binding  ribonuclease activity  extracellular region  extracellular space  lysosome  endoplasmic reticulum lumen  RNA catabolic process  ribonuclease T2 activity  lysosomal lumen  extracellular vesicular exosome  RNA phosphodiester bond hydrolysis  RNA phosphodiester bond hydrolysis  RNA phosphodiester bond hydrolysis, endonucleolytic  
Protein Interaction DatabaseRNASET2
Wikipedia pathwaysRNASET2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)RNASET2
SNP (GeneSNP Utah)RNASET2
SNP : HGBaseRNASET2
Genetic variants : HAPMAPRNASET2
1000_GenomesRNASET2 
ICGC programENSG00000026297 
CONAN: Copy Number AnalysisRNASET2 
Somatic Mutations in Cancer : COSMICRNASET2 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
DECIPHER (Syndromes)6:167343004-167370077
Mutations and Diseases : HGMDRNASET2
OMIM612944    612951   
MedgenRNASET2
GENETestsRNASET2
Disease Genetic AssociationRNASET2
Huge Navigator RNASET2 [HugePedia]  RNASET2 [HugeCancerGEM]
Genomic VariantsRNASET2  RNASET2 [DGVbeta]
Exome VariantRNASET2
dbVarRNASET2
ClinVarRNASET2
snp3D : Map Gene to Disease8635
DGIdb (Curated mutations)RNASET2
DGIdb (Drug Gene Interaction db)RNASET2
General knowledge
Homologs : HomoloGeneRNASET2
Homology/Alignments : Family Browser (UCSC)RNASET2
Phylogenetic Trees/Animal Genes : TreeFamRNASET2
Chemical/Protein Interactions : CTD8635
Chemical/Pharm GKB GenePA128394541
Clinical trialRNASET2
Cancer Resource (Charite)ENSG00000026297
Other databases
Probes
Litterature
PubMed35 Pubmed reference(s) in Entrez
CoreMineRNASET2
GoPubMedRNASET2
iHOPRNASET2

Bibliography

Mammalian Rh/T2/S-glycoprotein ribonuclease family genes: cloning of a human member located in a region of chromosome 6 (6q27) frequently deleted in human malignancies.
Trubia M, Sessa L, Taramelli R.
Genomics. 1997 Jun 1;42(2):342-4.
PMID 9192857
 
Cloning and characterization of a senescence inducing and class II tumor suppressor gene in ovarian carcinoma at chromosome region 6q27.
Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D, Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L, Magnanini C, Tibiletti MG, Bernasconi B, Daidone MG, Shridhar V, Smith DI, Negrini M, Barbanti-Brodano G, Taramelli R.
Oncogene. 2001a Feb 22;20(8):980-8.
PMID 11314033
 
Molecular cloning, tissue distribution, and chromosomal localization of the human homolog of the R2/Th/Stylar ribonuclease gene family.
Acquati F, Nucci C, Bianchi MG, Gorletta T, Taramelli R.
Methods Mol Biol. 2001b;160:87-101.
PMID 11265308
 
Tumor and metastasis suppression by the human RNASET2 gene.
Acquati F, Possati L, Ferrante L, Campomenosi P, Talevi S, Bardelli S, Margiotta C, Russo A, Bortoletto E, Rocchetti R, Calza R, Cinquetti R, Monti L, Salis S, Barbanti-Brodano G, Taramelli R.
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PMID 15809705
 
Characterization of RNASET2, the first human member of the Rh/T2/S family of glycoproteins.
Campomenosi P, Salis S, Lindqvist C, Mariani D, Nordstrom T, Acquati F, Taramelli R.
Arch Biochem Biophys. 2006 May 15;449(1-2):17-26. Epub 2006 Mar 13.
PMID 16620762
 
RNASET2 as a tumor antagonizing gene in a melanoma cancer model.
Monti L, Rodolfo M, Lo Russo G, Noonan D, Acquati F, Taramelli R.
Oncol Res. 2008;17(2):69-74.
PMID 18543608
 
RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection.
Henneke M, Diekmann S, Ohlenbusch A, Kaiser J, Engelbrecht V, Kohlschtter A, Kratzner R, Madruga-Garrido M, Mayer M, Opitz L, Rodriguez D, Ruschendorf F, Schumacher J, Thiele H, Thoms S, Steinfeld R, Nurnberg P, Gartner J.
Nat Genet. 2009 Jul;41(7):773-5. doi: 10.1038/ng.398. Epub 2009 Jun 14.
PMID 19525954
 
Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC.
Quan C, Ren YQ, Xiang LH, Sun LD, Xu AE, Gao XH, Chen HD, Pu XM, Wu RN, Liang CZ, Li JB, Gao TW, Zhang JZ, Wang XL, Wang J, Yang RY, Liang L, Yu JB, Zuo XB, Zhang SQ, Zhang SM, Chen G, Zheng XD, Li P, Zhu J, Li YW, Wei XD, Hong WS, Ye Y, Zhang Y, Wu WS, Cheng H, Dong PL, Hu DY, Li Y, Li M, Zhang X, Tang HY, Tang XF, Xu SX, He SM, Lv YM, Shen M, Jiang HQ, Wang Y, Li K, Kang XJ, Liu YQ, Sun L, Liu ZF, Xie SQ, Zhu CY, Xu Q, Gao JP, Hu WL, Ni C, Pan TM, Li Y, Yao S, He CF, Liu YS, Yu ZY, Yin XY, Zhang FY, Yang S, Zhou Y, Zhang XJ.
Nat Genet. 2010 Jul;42(7):614-8. doi: 10.1038/ng.603. Epub 2010 Jun 6.
PMID 20526339
 
Microenvironmental control of malignancy exerted by RNASET2, a widely conserved extracellular RNase.
Acquati F, Bertilaccio S, Grimaldi A, Monti L, Cinquetti R, Bonetti P, Lualdi M, Vidalino L, Fabbri M, Sacco MG, van Rooijen N, Campomenosi P, Vigetti D, Passi A, Riva C, Capella C, Sanvito F, Doglioni C, Gribaldo L, Macchi P, Sica A, Noonan DM, Ghia P, Taramelli R.
Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1104-9. doi: 10.1073/pnas.1013746108. Epub 2010 Dec 28.
PMID 21189302
 
rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA.
Haud N, Kara F, Diekmann S, Henneke M, Willer JR, Hillwig MS, Gregg RG, Macintosh GC, Gartner J, Alia A, Hurlstone AF.
Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1099-103. doi: 10.1073/pnas.1009811107. Epub 2011 Jan 3.
PMID 21199949
 
A genome-wide association study identifies two new risk loci for Graves' disease.
Chu X, Pan CM, Zhao SX, Liang J, Gao GQ, Zhang XM, Yuan GY, Li CG, Xue LQ, Shen M, Liu W, Xie F, Yang SY, Wang HF, Shi JY, Sun WW, Du WH, Zuo CL, Shi JX, Liu BL, Guo CC, Zhan M, Gu ZH, Zhang XN, Sun F, Wang ZQ, Song ZY, Zou CY, Sun WH, Guo T, Cao HM, Ma JH, Han B, Li P, Jiang H, Huang QH, Liang L, Liu LB, Chen G, Su Q, Peng YD, Zhao JJ, Ning G, Chen Z, Chen JL, Chen SJ, Huang W, Song HD; China Consortium for Genetics of Autoimmune Thyroid Disease.
Nat Genet. 2011 Aug 14;43(9):897-901. doi: 10.1038/ng.898.
PMID 21841780
 
RNASET2--an autoantigen in anaplastic large cell lymphoma identified by protein array analysis.
Patel S, Chen H, Monti L, Gould E, Haralambieva E, Schmid J, Toomey D, Woessmann W, Roncador G, Hatton CS, Liggins AP, Taramelli R, Banham AH, Acquati F, Murphy D, Pulford K.
J Proteomics. 2012 Sep 18;75(17):5279-92. doi: 10.1016/j.jprot.2012.06.009. Epub 2012 Jun 23.
PMID 22732457
 
Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis.
Acquati F, Lualdi M, Bertilaccio S, Monti L, Turconi G, Fabbri M, Grimaldi A, Anselmo A, Inforzato A, Collotta A, Cimetti L, Riva C, Gribaldo L, Ghia P, Taramelli R.
Proc Natl Acad Sci U S A. 2013 May 14;110(20):8140-5. doi: 10.1073/pnas.1222079110. Epub 2013 Apr 29.
PMID 23630276
 
Genome-wide association study of Crohn's disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations.
Yang SK, Hong M, Zhao W, Jung Y, Baek J, Tayebi N, Kim KM, Ye BD, Kim KJ, Park SH, Lee I, Lee EJ, Kim WH, Cheon JH, Kim YH, Jang BI, Kim HS, Choi JH, Koo JS, Lee JH, Jung SA, Lee YJ, Jang JY, Shin HD, Kang D, Youn HS, Liu J, Song K.
Gut. 2014 Jan;63(1):80-7. doi: 10.1136/gutjnl-2013-305193. Epub 2013 Jul 14.
PMID 23850713
 
Stress-induced RNASET2 overexpression mediates melanocyte apoptosis via the TRAF2 pathway in vitro.
Wang Q, Jiang M, Wu J, Ma Y, Li T, Chen Q, Zhang X, Xiang L.
Cell Death Dis. 2014 Jan 23;5:e1022. doi: 10.1038/cddis.2013.539.
PMID 24457966
 
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Contributor(s)

Written02-2007Francesco Acquati, Paola Campomenosi
-
Updated06-2014Francesco Acquati
Dept of Theoretical and Applied Sciences, University of Insubria - Varese, Italy

Citation

This paper should be referenced as such :
Acquati F
RNASET2 (ribonuclease T2);
Atlas Genet Cytogenet Oncol Haematol. June 2014
Free online version   Free pdf version   [Bibliographic record ]
Atlas Genet Cytogenet Oncol Haematol. June 2014
URL : http://AtlasGeneticsOncology.org/Genes/RNASET2ID518ch6q27.html

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