Download Gene Section RTN4 (reticulon 4) Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
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Gene Section
Mini Review
RTN4 (reticulon 4)
Masuo Yutsudo
Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita 565-0871, Japan
Published in Atlas Database: January 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/RTN4ID42182ch2p16.html
DOI: 10.4267/2042/38416
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
NSP; NSP-CL; Nbla00271; Nbla10545; RTN-X;
RTN4-A; RTN4-B1; RTN4-B2; RTN4-C
Location: 2p16.3
Local order: Between FLJ42562 and FLJ31438.
Identity
Hugo: RTN4
Other names: ASY; NI220/250; NOGO; NOGO-A;
Fig 1. Local order.
Fig 2. Genomic structure and transcriptional isoforms.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2)
128
RTN4 (reticulon 4)
Yutsudo M
DNA/RNA
Implicated in
Description
Various cancers
The RTN4 gene spans about 75kb, and contains 9
major exons and several different cap sites (Fig. 2a).
Note: Down-regulation of RTN4 expression was
observed in small cell lung carcinomas and adult T-cell
leukemia/lymphomas, and RTN3, one of RTN4
interacting
proteins,
was
over-expressed
in
astrocytomas, suggesting involvement of RTN4 (and
RTN3) in certain types of tumorigenesis. However,
increased incidence of tumor formation has not been
observed in RTN4 knock out mice.
RTN4 is also suspected to involve in schizophrenia and
neuronal degenerative diseases.
Transcription
Three major, RTN4-A, B1 and C, (Fig. 2b) and several
minor transcriptional isoforms result from alternative
splicing and/or differential promoter usage. Although
RTN4 mRNA is ubiquitously expressed, the expression
of isoforms is tissue-specific, for example, RTN4-A
and C in brain, RTN4-C in muscle, and RTN4-B1 in
many other tissues.
References
Protein
Chen MS, Huber AB, van der Haar ME, Frank M, Schnell L,
Spillmann AA, Christ F, Schwab ME. Nogo-A is a myelinassociated neurite outgrowth inhibitor and an antigen for
monoclonal antibody IN-1. Nature 2000;403:434-439.
Description
Proteins with different sizes are synthesized from
different mRNA isoforms: RTN4-A, 129.9 kDa (1192
amino acids); RTN4-B1, 40.3 kDa (373 amino acids);
RTN4-B2, 42.3 kDa (392 amino acids); RTN4-C, 22.4
kDa (199 amino acids). All RTN4 protein isoforms
retain a common C-terminal domain containing two
trans-membrane domains and an endoplasmic
reticulum (ER)-retrieval motif.
GrandPré T, Nakamura F, Vartanian T, Strittmatter SM.
Identification of the Nogo inhibitor of axon regeneration as a
Reticulon protein. Nature 2000;403:439-444.
Prinjha R, Moore SE, Vinson M, Blake S, Morrow R, Christie
G, Michalovich D, Simmons DL, Walsh FS. Inhibitor of neurite
outgrowth in humans. Nature 2000;403:383-384.
Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y. A
novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on
endoplasmic reticulum and reduces their anti-apoptotic activity.
Oncogene 2000;19:5736-5746.
Expression
Ubiquitously expressed (see Transcription).
Yang J, Yu L, Bi AD, Zhao SY. Assignment of the human
reticulon 4 gene (RTN4) to chromosome 2p14---2p13 by
radiation hybrid mapping. Cytogenet Cell Genet 2000;88:101102.
Localisation
RTN4 protein localizes predominantly in the ER and,
to a lesser extent, in cytoplasmic membrane.
Fournier AE, GrandPré T, Strittmatter SM. Identification of a
receptor mediating Nogo-66 inhibition of axonal regeneration.
Nature 2001;409:341-346.
Function
Li Q, Qi B, Oka K, Shimakage M, Yoshioka N, Inoue H, Hakura
A, Kodama K, Stanbridge EJ, Yutsudo M. Link of a new type of
apoptosis-inducing gene ASY/Nogo-B to human cancer.
Oncogene 2001;20:3929-3936.
Although definitive functional mechanisms of RTN4
have not yet been clarified, RTN4 protein interacts with
several other proteins, including RTN1, RTN3,
DP1/Yop1p, BACE1, and Nogo receptor (NogoR).
Interaction with DP1/Yop1p, an ER membrane protein,
may be necessary for maintenance or stabilization of
tubular ER. Binding with BACE1 (beta-amyloid
converting enzyme 1) results in reduction in BACE1
activity and production of amyloid-beta. RTN4 also
interacts with NogoR, and may lead to activation of
RhoA and inhibition of neuronal regeneration in central
nervous system. Further, overexpression of RTN4 may
cause ER stress and apoptosis in certain cells.
Dupuis L, Gonzalez de Aguilar JL, di Scala F, Rene F, de
Tapia M, Pradat PF, Lacomblez L, Seihlan D, Prinjha R, Walsh
FS, Meininger V, Loeffler JP. Nogo provides a molecular
marker for diagnosis of amyotrophic lateral sclerosis. Neurobiol
Dis 2002;10:358-365.
Novak G, Kim D, Seemen P, Tallerico T. Schizophrenia and
Nogo: elevated mRNA in cortex, and high prevalence of a
homozygous CAA insert. Brain Res Mol Brain Res
2002;107:183-189.
Kim JE, Li S, GrandPré T, Qiu D, Strittmatter SM. Axon
regeneration in young adult mice lacking Nogo-A/B. Neuron
2003;38:187-190.
Homology
Oertle T, Huber C, van der Putten H, Schwab ME. Genomic
structure and functional characterization of the promoters of
human and mouse nogo/rtn4. J Mol Biol 2003;325:299-323.
Four reticulon family members (RTN1, RTN2, RTN3
and RTN4) have been identified. They possess a highly
conserved C-terminal domain named reticulon
homology domain.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2)
Oertle T, Schwab ME. Nogo and its partners. Trends Cell Biol
2003;13:187-194. (Review).
129
RTN4 (reticulon 4)
Yutsudo M
Qi B, Qi Y, Watari A, Yoshioka N, Inoue H, Minemoto Y,
Yamashita K, Sasagawa T, Yutsudo M. Pro-apoptotic
ASY/Nogo-B protein associates with ASYIP. J Cell Physiol
2003;196:312-318.
corticospinal tract regeneration in vivo. Proc Natl Acad Sci
USA 2005;102:1205-1210.
Chen Y, Tang X, Cao X, Chen H, Zhang X. Human Nogo-C
overexpression induces HEK293 cell apoptosis via a
mechanism that involves JNK-c-Jun pathway. Biochem
Biophys Res Commun 2006;348:923-928.
Simonen M, Pedersen V, Weinmann O, Schnell L, Buss A,
Ledermann B, Christ F, Sansig G, van der Putten H, Schwab
ME. Systemic deletion of the myelin-associated outgrowth
inhibitor Nogo-A improves regenerative and plastic responses
after spinal cord injury. Neuron 2003;38:201-211.
Kuang E, Wan Q, Li X, Zou T, Qi Y. ER stress triggers
apoptosis induced by Nogo-B/ASY overexpression. Exp Cell
Res 2006;312:1983-1988.
Watari A, Yutsudo M. Multi-functional gene ASY/Nogo/RTNX/RTN4: Apoptosis, tumor suppression, and inhibition of
neuronal regeneration. Apoptosis 2003;8:5-9. (Review).
Murayama KS, Kametani F, Saito S, Kume H, Akiyama H,
Araki W. Reticulons RTN3 and RTN4-B/C interact with BACE1
and inhibit its ability to produce amyloid beta-protein. Eur J
Neurosci 2006;24:1237-1244.
Zheng B, Ho C, Li S, Keirstead H, Steward O, Tessier-Lavigne
M. Lack of enhanced spinal regeneration in Nogo-deficient
mice. Neuron 2003;38:213-224.
Novak G, Tallerico T. Nogo A, B and C expression in
schizophrenia, depression and bipolar cortex, and correlation
of Nogo expression with CAA/TATC polymorphism in 3-UTR.
Brain Res 2006;1120:161-171.
Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE,
Fulton D, Tempst P, Strittmatter SM, Sessa WC. A new role for
Nogo as a regulator of vascular remodeling. Nat Med
2004;10:382-388.
Schwab JM, Tuli SK, Failli V. The Nogo receptor complex:
confining molecules to molecular mechanisms. Trends Mol
Med 2006;12:293-297. (Review).
He W, Lu Y, Oahwash I, Hu XY, Chang A, Yan R. Reticulon
family members modulate BACE1 activity and amyloid-beta
peptide generation. Nat Med 2004;10:959-965.
Shimakage M, Inoue N, Ohshima K, Kawahara K, Oka T,
Yasui K, Matsumoto K, Inoue H, Watari A, Higashiyama S,
Yutsudo M. Down-regulation of ASY/Nogo transcription
associated
with
progression
of
adult
T-cell
leukemia/lymphoma. Int J Cancer 2006;119:1648-1653.
Huang X, Yang H, Zhou Y, Liu J, Yin B, Peng X, Qiang B,
Yuan J. Overexpression of human reticulon 3 (hRTN3) in
astrocytoma. Clin Neuropathol 2004;23:1-7.
Sinibaldi L, De Luca A, Bellacchio E, Conti E, Pasini A,
Paloscia A, Spalletta G, Caltagirone C, Pizzuti A, Dallapiccola
B. Mutations of the Nogo-66 receptor (RTN4R) gene in
schizophrenia. Human Mutat 2004;24:534-535.
Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA. A
class of membrane proteins shaping the tubular endoplasmic
reticulum. Cell 2006;124:573-586.
Yan R, Shi Q, Hu X, Zhou X. Reticulon proteins: emerging
players in neurodegenerative diseases. Cell Mol Life Sci
2006;63:877-889. (Review).
Rousseau S, Peggie M, Campbell DG, Nebreda AR, Cohen P.
Nogo-B is a new physiological substrate for MAPKAP-K2.
Biochem J 2005;391:433-440.
This article should be referenced as such:
Yutsudo M. RTN4 (reticulon 4). Atlas Genet Cytogenet Oncol
Haematol.2007;11(2):128-130.
Zheng B, Atwal J, Ho C, Case L, He XL, Garcia KC, Steward
O, Tessier-Lavigne M. Genetic deletion of the Nogo receptor
does not reduce neurite inhibition in vitro or promote
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2)
130