Download Gene Section RBM5 (RNA binding motif protein 5) in Oncology and Haematology

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Gene Section
Review
RBM5 (RNA binding motif protein 5)
Mirna Mourtada-Maarabouni
School of Life Sciences, Keele University, Keele ST5 5BG, UK
Published in Atlas Database: February 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/RBM5ID42069ch3p21.html
DOI: 10.4267/2042/38444
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Transcription
Identity
Full length RBM5 has 3.1 Kb, 2448 bp open reading
frame. The gene encodes a number of alternative splice
variants, identified by reverse transcription polymerase
chain reaction. One splice variant lacks exon 6,
RBM5delta6. Three other RNA splice variants retain
intronic sequences, RBM5+5+6 retains introns 5 and 6,
RBM5+6 retains intron 6 and clone 26 which is a
partial cDNA containing an open reading frame and
terminates within intron 6. A 326 bp antisense cDNA
that maps to the intronic region of RBM5, je2, has also
been identified. Both, RBM5delta6 and clone 26
cDNAs have been cloned.
Hugo: RBM5
Other names: LUCA-15; H37; G15
Location: 3p21.3
Note: 3p21.3 is a putative human lung cancer tumor
suppressor region. RBM5/LUCA-15 is a putative tumor
suppressor gene.
DNA/RNA
Description
The gene spans about 30.03 Kb. Orientation plus
strand. At least 25 exons.
RBM5/LUCA-15 splice variants. Boxes represent the exons, intronic sequences are represented by horizontal lines. The arrows point to
the STOP codon in the protein coding sequence.
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RBM5 (RNA binding motif protein 5)
Mourtada-Maarabouni M
Function
Protein
RBM5/LUCA-15 is among the 35 genes located within
the 370 kb overlapping lung cancer homozygous
deletion region at 3p21.3. RBM5 has been implicated
in the control of cell death by apoptosis and cell
proliferation. RBM5's involvement in apoptosis and
malignancy has been the focus of many recent studies,
with all results converging on a role for RBM5/LUCA15 as a Tumor Suppressor Gene (TSG). RBM5 splice
variants have been shown to function as regulators of
apoptosis. Stable expression of Je2, in human T-cell
lines CEM-C7 and Jurkat produced marked inhibition
of Fas-mediated apoptosis and conferred protection
from apoptosis induced by other stimuli. RBM5delta6
inhibits CD95-mediated apoptosis as well as
accelerating cell proliferation.
Overexpression of the full length RBM5 in CEM-C7
and Jurkat T-cell lines suppressed cell proliferation
both by inducing apoptosis and by inducing cell cycle
arrest in G1. Consistently, RBM5/LUCA-15
overexpression also inhibited human lung cancer cell
growth (A549 non-small cell lung cancer line) by
increasing apoptosis and inducing cell cycle arrest in
G1. This inhibition of cell growth was reported to be
associated with decreased cyclin A and phosphorylated
RB and an increase in the level of the proapototic
protein Bax. Introducing RBM5/LUCA-15 into breast
cancer cells that had 3p21-22 deletions reduced both
anchorage-dependent
and
anchorage-independent
growth. RBM5/LUCA-15 also is reported to suppress
anchorage-dependent
and
anchorage-independent
growth in A9 mouse fibrosarcoma cells and to inhibit
their tumour forming activity in nude mice.
RBM5/LUCA-15 was one of the nine genes downregulated in metastasis and it has been included in the
17 common gene signature associated with metastasis
identified in multiple solid tumour types. Solid tumours
carrying this gene expression signature had high rates
of metastasis and poor clinical outcome. Microarraybased analysis of changes in gene expression caused by
the modulation of the level of RBM5/LUCA-15 were
carried out. Among 5603 genes on cDNA microarray,
35 genes, well known for their roles in the cell cycle as
well as in apoptosis, were found to be differentially
expressed as a result of RBM5/LUCA-15
overexpression in CEM-C7 cells.
These RBM5/LUCA-15 modulated genes include a
number of cyclin-dependent kinase complexes, most
notably CDK2 and three putative oncogenes which are
down-regulated by RBM5/LUCA-15. These are Pim-1,
a serine/threonine kinase, ITPA (inosine triphosphate
pyrophosphatase) and Amplified in Breast cancer 1
(AIB1). Other functionally important genes modulated
by RBM5/LUCA-15 are well established to play
specific anti apoptotic roles such as BIRC4 (AIP3),
Description
Full length RBM5 encodes a protein with a molecular
mass of about 90 kDa (815 amino acids). The protein
has two RNA Binding Domains (RBD), also
recognized as RNA Recognition Motif (RRM). RBM5
structure also features other functional motifs, which
includes two putative zinc-finger DNA binding motifs,
two bipartite nuclear localisation signals and a G-patch
domain (a conserved domain in eukaryotic RNAprocessing proteins and type D retroviral polyproteins),
suggesting a role for RBM5/LUCA-15 in RNA
processing. In addition, the C-terminal region of
RBM5/LUCA-15 contains several domains including a
glutamine rich domain (362-385), which is thought to
serve as protein-protein interaction site in certain RNAand DNA- binding proteins.
RBM5delta6 encodes a protein of 17 kDa, due to a
frameshift mutation caused by the deletion of exon 6.
The only functional motif retained by this truncated
protein is the arginine/glycine-rich amino terminal
region. A putative 21 kDa is reported to be encoded by
RBM5+5+6 and clone 26, as revealed by an in vitro
transcription/translation study in rabbit reticulocyte
lysate.
Expression
Full length RBM5 and its alternative splice variants
RNA are widely expressed in both primary tissue and
cell lines. Northern blot analysis revealed higher
expression in skeletal and heart muscles and pancreas.
The expression of the full length RBM5 mRNA is
reported to be high in adult thymus and low in the
foetal thymus, suggesting that its expression is
developmentally regulated. Full length RBM5/LUCA15 is reported to be down-regulated in breast cancer
specimens, in 82% of primary non-small-cell lung
carcinoma specimens and in many lung cancer cell
lines and in vestibular schwannomas (27 fold
reduction). The expression of RBM5delta6 RNA is
highest in transformed cells. The full length RBM5
protein is ubiquitously expressed in human tissues. It
was found to be downregulated in 73% of primary nonsmall-cell lung carcinoma specimens compared to
normal adjacent tissue. RBM5/LUCA-15 was one of
the antigens identified by autologous antibody in
patients with renal carcinoma. Overexpression of je2,
the 326 bp antisense sequence, resulted in the
downregulation of the RBM5 protein (95 kDa) and the
upregulation of the 17 kDa protein (RBM5delta6).
Localisation
RBM5 protein includes bipartite nuclear localisation
signals suggesting its localisation to the nucleus.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
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RBM5 (RNA binding motif protein 5)
Mourtada-Maarabouni M
BIRC3 (cIAP2, MIHC), Mcl-1, a member of the Bcl-2
family of apoptosis suppressors, and TRAF1,
supporting a role for RBM5/LUCA-15 in apoptosis.
Other genes upregulated by RBM5/LUCA-15 include
Stat5b, Annexin I and Bone Morphogenetic Protein 5
(BMP5), implicated in apoptosis, immunosuppression
and organ development respectively.
References
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Homology
RBM5 shares 30% amino acid sequence homology
with its immediate telomeric neighbor, the putative
tumor suppressor gene RBM6. Another RNA Binding
Motif protein that shares high homology with RBM5
(53% at the amino acid level) is RBM10. The RBM10
gene is located on the X chromosome at p11.23. No
function has yet been determined for RBM10. The
mouse RBM5 gene is 90% identical on cDNA level
and 97% on protein level. The fly proteome contain
three similar proteins, of which CG4887 gene product
shows 43% similarity. The rat binding protein S1-1 has
similar domain structure and is close in amino acid
sequence to RBM5.
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Mutations
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Note: Mutations in the RMB5 gene have not been
found in lung cancer. RBM5 is reported to be
downregulated in RAS-transformed Rat-1 cells, in
samples from breast cancer, in human schwannomas
and in about 75% of primary lung cancers specimens.
RBM5 was one of the nine genes down-regulated in
metastasis in primary tumors and it has been included
in the 17 common gene signature associated with
metastasis identified in multiple solid tumour types.
Solid tumours carrying this gene expression signature
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Implicated in
Drabkin HA, West JD, Hotfilder M, Heng YM, Erickson P,
Calvo R, Dalmau J, Gemmill RM, Sablitzky F. DEF-3(g16/NYLU-12), an RNA binding protein from the 3p21.3 homozygous
deletion region in SCLC. Oncogene 1999;18(16):2589-2597.
Lung cancer and many other cancers
Disease
RBM5 is located at the human chromosomal locus
3p21.3, which is strongly associated with lung cancer
and many other cancers, including head and neck,
renal, breast and female genital tract. More than 90% of
freshly microdissected primary lung cancers display
loss of heterozygosity (LOH) of 3p21.3. RBM5 is
implicated in apoptosis and in cell cycle regulation.
Oncogenesis
The ability of RBM5/LUCA-15 to inhibit the growth of
transformed cells fulfils one of the criteria for a tumor
suppressor. The simultaneous changes in proliferation
and inhibition of apoptosis brought about by
dysregulation of the RBM5/LUCA-15 locus are likely
to be of major significance in oncogenesis.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
Hotfilder M, Baxendale S, Cross MA, and Sablitzky F. Def-2, 3, -6 and -8, novel mouse genes differentially expressed in the
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Old LJ. Antigens recognized by autologous antibody in patients
with renal-cell carcinoma. Int J Cancer 1999;83(4):456-464.
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A, Voutsinas G, Hulsbeek MM, Draaijers TG, Looman MW,
Kok K, Naylor SL, Buys CH. A comparison of genomic
structures and expression patterns of two closely related
flanking genes in a critical lung cancer region at 3p21.3. Eur J
Hum Genet 1999;7(4):478-486.
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This article should be referenced as such:
Mourtada-Maarabouni M. RBM5 (RNA binding motif protein 5).
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Mourtada-Maarabouni M, Sutherland LC, Meredith JM,
Williams GT. Simultaneous acceleration of the cell cycle and
suppression of apoptosis by splice variant delta-6 of the
candidate tumour suppressor LUCA-15/RBM5. Genes Cells
2003;8(2):109-119.
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