Download Gene Section MAP4 (microtubule-associated protein 4) Atlas of Genetics and Cytogenetics

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in Oncology and Haematology
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Gene Section
Mini Review
MAP4 (microtubule-associated protein 4)
Eva Maria Murga Penas, Judith Dierlamm
Dept Oncology, Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum - University
Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Martinistr 52, 20246 Hamburg,
Germany (EMM, JD)
Published in Atlas Database: June 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/MAP4ID44410ch3p21.html
DOI: 10.4267/2042/44754
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
interaction with the promoter region of MAP4.
Overexpression of MAP4 markedly inhibits P53
mediated apoptosis (Murphy et al., 1996; Murphy et al.,
1999).
Identity
Other names: MAP-4; MGC8617
HGNC (Hugo): MAP4
Location: 3p21.31
Transcription
Centromere to telomere transcription. The multiple
MAP4 isoforms are generated by alternative splicing
(see figure below).
Protein
Description
The protein encoded by the MAP4 gene is the major
microtubule-associated protein in non-neuronal tissues
and belongs to the group of microtubule-associated
proteins (MAPs) of the MAP2/Tau family (Bulinski et
al., 1980; Chapin et al., 1995). MAP4 contains a
projection domain in its extreme N-terminus and a
microtubule binding domain (MTB) in its carboxylterminal portion. The MTB domain consists of 3
subdomains, a Proline-rich region, a Repeat region
consisting of an Assembly-Promoting (AP) sequence of
18-amino acids (Aas) residues, and a Tail region rich in
hydophobic and acidic Aas. Three to five repeats of the
AP sequence have been described in MAP4 (Aizawa et
al., 1990). In vitro experiments with bovine MAP4
have shown that the number of repeat sequences affects
the microtubule surface properties (Tokuraku et al.,
2003).
MAP4 gene (3p21). FISH on normal lymphocytes using the
BAC clone 395P16 on 3p21 obtained from the RPCI-11 library
(Roswell Park Cancer Institute, Buffalo, NY). BAC 395P16
contains sequences derived immediately downstream of the
MAP4 gene and is translocated to the partner chromosome in
case of a translocation involving MAP4.
DNA/RNA
Description
MAP4 is encoded by a single-copy gene spanning a
region of ~238 kb of genomic DNA. Five alternative
transcripts have been described (West et al., 1991).
MAP4 is down-regulated by P53 at the transcriptional
level. The repression of MAP4 by P53 is exerted by
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
Expression
Widespread tissue distribution but absent from neurons
(Bulinski and Borisy, 1980; Aizawa et al., 1990;
Chapin and Bulinski, 1991; West et al., 1991).
460
MAP4 (microtubule-associated protein 4)
Murga Penas EM, Dierlamm J
mRNA splice variants of MAP4. Nucleotide assignation according to GenBank sequence NT_022517 REGION:
47832180..48070769 GPS_000125239 (Homo sapiens chromosome 3 genomic contig, GRCh37 reference primary
assembly).
Schematic representation of the MAP4 protein.
Localisation
Implicated in
Cytoplasmic.
Diffuse large B-cell non-Hodgkin's
lymphoma (DLBCL), centroblastic
subtype
Function
MAP4 binds to, polymerizes, and stabilizes
microtubules and is thought to regulate microtubule
dynamics during the cell cycle. In eukaryotic cells, the
onset of M phase is regulated by the p34cdc2/Cyclin B
complex, which controls changes in microtubule
dynamic properties at the G2 to M phase transition of
the cell cycle The control of the microtubule
reorganization at mitosis is supposed to be directly
regulated by phosphorylation of MAP4 by the p34cdc2
kinase activity (Ookata et al., 1997).
Disease
Non-reciprocal
der(18)t(3;18)(p21;q21)/MALT1MAP4 translocation.
Cytogenetics
Rearrangements of the MALT1 gene by the
translocations t(11;18)(q21;q21)/API2-MALT1 and
t(14;18)(q32;q21)/IGH-MALT1 are the most frequent
structural chromosomal abnormalities in MALT
lymphomas and lead to an activation of the NF-kB
pathway (Dierlamm et al., 1999; Uren et al., 2000;
Lucas et al., 2001; Streubel et al., 2003). In both
translocations the caspase-like domain of MALT1 is
invariabily involved.
Homology
About 80% similarity/70% identity among the human,
mouse, and bovine Aas sequences (West et al., 1991).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
461
MAP4 (microtubule-associated protein 4)
Murga Penas EM, Dierlamm J
Schematic representation of the localization of the breakpoints in MALT1 and MAP4 and the corresponding fusion product.
homologous to the microtubule-binding domains of neuronal
MAP2 and tau. J Cell Sci. 1991 Jan;98 ( Pt 1):27-36
Unlike the API2-MALT1 and IGH-MALT1 products,
the MALT1-MAP4 fusion product does not involve the
caspase-like domain, which is essential for activation of
NF-kB. The absence of the caspase like domain in the
MALT1-MAP4 fusion product distinguishes this novel
gene fusion, MALT1-MAP4, from the t(11;18)/API2MALT1 and the t(14;18)/IGH-MALT1 and points to a
new mechanism of deregulation of MALT1 (Murga
Penas et al., 2006).
Hybrid/Mutated gene
The 5'MALT1-3'MAP4 fusion product is the result of
an unbalanced translocation that fuses "in frame" the
exon 9 of MALT1 located on 18q21 to exon 9 of
MAP4 located on 3p21 (Murga Penas et al., 2006). The
MALT1-MAP4 fusion is located on the derivative
chromosome 18 and due to a partial deletion of
MALT1 sequences telomeric to exon 9 the reciprocal
transcript MAP4-MALT1 is absent.
The MALT1-MAP4 chimeric product corresponds to a
fusion of the MALT1 gene at nucleotide 1276
(Genebank Accession No. NM_006785) to the MAP4
gene at nucleotide 2469 (Genebank Accession No.
NM_002375).
West RR, Tenbarge KM, Olmsted JB. A model for microtubuleassociated protein 4 structure. Domains defined by
comparisons of human, mouse, and bovine sequences. J Biol
Chem. 1991 Nov 15;266(32):21886-96
Chapin SJ, Lue CM, Yu MT, Bulinski JC. Differential
expression of alternatively spliced forms of MAP4: a repertoire
of structurally different microtubule-binding domains.
Biochemistry. 1995 Feb 21;34(7):2289-301
Murphy M, Hinman A, Levine AJ. Wild-type p53 negatively
regulates the expression of a microtubule-associated protein.
Genes Dev. 1996 Dec 1;10(23):2971-80
Ookata K, Hisanaga S, Sugita M, Okuyama A, Murofushi H,
Kitazawa H, Chari S, Bulinski JC, Kishimoto T. MAP4 is the in
vivo substrate for CDC2 kinase in HeLa cells: identification of
an M-phase specific and a cell cycle-independent
phosphorylation site in MAP4. Biochemistry. 1997 Dec
16;36(50):15873-83
Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M,
Hernandez JM, Hossfeld DK, De Wolf-Peeters C, Hagemeijer
A, Van den Berghe H, Marynen P. The apoptosis inhibitor gene
API2 and a novel 18q gene, MLT, are recurrently rearranged in
the t(11;18)(q21;q21) associated with mucosa-associated
lymphoid tissue lymphomas. Blood. 1999 Jun 1;93(11):3601-9
Murphy M, Ahn J, Walker KK, Hoffman WH, Evans RM, Levine
AJ, George DL. Transcriptional repression by wild-type p53
utilizes histone deacetylases, mediated by interaction with
mSin3a. Genes Dev. 1999 Oct 1;13(19):2490-501
References
Bulinski JC, Borisy GG. Widespread distribution of a 210,000
mol wt microtubule-associated protein in cells and tissues of
primates. J Cell Biol. 1980 Dec;87(3 Pt 1):802-8
Uren AG, O'Rourke K, Aravind LA, Pisabarro MT, Seshagiri S,
Koonin EV, Dixit VM. Identification of paracaspases and
metacaspases: two ancient families of caspase-like proteins,
one of which plays a key role in MALT lymphoma. Mol Cell.
2000 Oct;6(4):961-7
Aizawa H, Emori Y, Mori A, Murofushi H, Sakai H, Suzuki K.
Functional analyses of the domain structure of microtubuleassociated protein-4 (MAP-U). J Biol Chem. 1991 May
25;266(15):9841-6
Lucas PC, Yonezumi M, Inohara N, McAllister-Lucas LM,
Abazeed ME, Chen FF, Yamaoka S, Seto M, Nunez G. Bcl10
and MALT1, independent targets of chromosomal translocation
in malt lymphoma, cooperate in a novel NF-kappa B signaling
pathway. J Biol Chem. 2001 Jun 1;276(22):19012-9
Chapin SJ, Bulinski JC. Non-neuronal 210 x 10(3) Mr
microtubule-associated protein (MAP4) contains a domain
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
462
MAP4 (microtubule-associated protein 4)
Murga Penas EM, Dierlamm J
Streubel B, Lamprecht A, Dierlamm J, Cerroni L, Stolte M, Ott
G, Raderer M, Chott A. T(14;18)(q32;q21) involving IGH and
MALT1 is a frequent chromosomal aberration in MALT
lymphoma. Blood. 2003 Mar 15;101(6):2335-9
ML, Dierlamm J. A novel fusion of the MALT1 gene and the
microtubule-associated protein 4 (MAP4) gene occurs in
diffuse large B-cell lymphoma. Genes Chromosomes Cancer.
2006 Sep;45(9):863-73
Tokuraku K, Matsushima K, Matui T, Nakagawa H, Katsuki M,
Majima R, Kotani S. The number of repeat sequences in
microtubule-associated protein 4 affects the microtubule
surface properties. J Biol Chem. 2003 Aug 8;278(32):29609-18
This article should be referenced as such:
Murga Penas EM, Dierlamm J. MAP4 (microtubule-associated
protein 4). Atlas Genet Cytogenet Oncol Haematol. 2010;
14(5):460-463.
Murga Penas EM, Kawadler H, Siebert R, Frank M, Ye H, Hinz
K, Becher C, Hummel M, Barth TF, Bokemeyer C, Stein H,
Trümper L, Möller P, Marynen P, Du MQ, Yang X, Hansmann
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
463