Download Gene Section RNASET2 (ribonuclease T2) Atlas of Genetics and Cytogenetics

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Gene Section
Review
RNASET2 (ribonuclease T2)
Francesco Acquati
Dept of Theoretical and Applied Sciences, University of Insubria - Varese, Italy (FA)
Published in Atlas Database: June 2014
Online updated version : http://AtlasGeneticsOncology.org/Genes/RNASET2ID518ch6q27.html
DOI: 10.4267/2042/56433
This article is an update of :
Acquati F, Campomenosi P. RNASET2 (ribonuclease T2). Atlas Genet Cytogenet Oncol Haematol 2007;11(3):219-221.
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2015 Atlas of Genetics and Cytogenetics in Oncology and Haematology
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.
Abstract
Review on RNASET2, with data on DNA/RNA, on
the protein encoded and where the gene is
implicated.
Identity
Other names: RNASE6PL, RP11-514O12.3,
bA514O12.3
HGNC (Hugo): RNASET2
Location: 6q27
Local order: Telomeric to RPS6KA2, centromeric
to FGFR1OP.
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RNASET2 (ribonuclease T2)
Acquati F
I-IX: RNASET2 exons; Red boxes: CAS I and CAS II catalytic sites; Dark green boxes: untranslated regions.
7p11.2. The expression pattern of this pseudogene
is not known.
DNA/RNA
Description
Protein
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.
Description
The aminoacid sequence of RNASET2 depicts a
typical member of the highly conserved Rh7T2/S
family of extracellular, acid ribonucleases. The Xray 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.
Transcription
The RNASET2 gene is transcribed in the telomereto-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.
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 Cterminal proteolytic products have also been
observed intracellularly in several human cancer
cell lines.
Pseudogene
A processed pseudogene showing 85% identity
with RNASET2 mRNA maps to chromosome
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.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(4)
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RNASET2 (ribonuclease T2)
Acquati F
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.
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).
Somatic
Function
A few common polymorphisms in exons 1, 8 and 9
have been described. In general, coding mutations
are rarely found in tumor samples.
Biochemical function: RNASET2 is an acid
ribonuclease with optimal activity at pH 5 and
preferential cleavage of poly-A and poly-U homopolyribonucleotides.
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 stressinduced 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.
Implicated in
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 knockingdown 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.
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.
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-
Germinal
A common exon-9 missense C708T germline
mutation has been described but no evidence for an
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(4)
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RNASET2 (ribonuclease T2)
Acquati F
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.
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.
References
Trubia M, Sessa L, Taramelli R. Mammalian Rh/T2/Sglycoprotein ribonuclease family genes: cloning of a
human member located in a region of chromosome 6
(6q27) frequently deleted in human malignancies.
Genomics. 1997 Jun 1;42(2):342-4
Acquati F, Morelli C, Cinquetti R, Bianchi MG, Porrini D,
Varesco L, Gismondi V, Rocchetti R, Talevi S, Possati L,
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Shridhar V, Smith DI, Negrini M, Barbanti-Brodano G,
Taramelli R. Cloning and characterization of a senescence
inducing and class II tumor suppressor gene in ovarian
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Feb 22;20(8):980-8
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.
Acquati F, Nucci C, Bianchi MG, Gorletta T, Taramelli R.
Molecular cloning, tissue distribution, and chromosomal
localization of the human homolog of the R2/Th/Stylar
ribonuclease
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Methods
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2001b;160:87-101
Acquati F, Possati L, Ferrante L, Campomenosi P, Talevi
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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 ALKnegative ALCL-associated antigen.
Campomenosi P, Salis S, Lindqvist C, Mariani D,
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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.
Atlas Genet Cytogenet Oncol Haematol. 2015; 19(4)
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This article should be referenced as such:
Acquati F. RNASET2 (ribonuclease T2). Atlas Genet
Cytogenet Oncol Haematol. 2015; 19(4):240-244.
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