Download Gene Section MEF2D (myocyte enhancer factor 2D) Atlas of Genetics and Cytogenetics

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MEF2D (myocyte enhancer factor 2D)
Victor Prima, Lyudmyla G Glushakova, Stephen P Hunger
University of Florida College of Medicine, Gainesville, FL 32610, USA (VP, LGG); Children's Hospital and
the Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA
(SPH)
Published in Atlas Database: October 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/MEF2DID43636ch1q22.html
DOI: 10.4267/2042/44827
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
MADS-box on N terminus (2-78 aa, MAD MEF2 like);
the 29-aa MEF2 domain immediately C-terminal to the
MADS- box (unique to the MEF2 factors); C-terminal
transcriptional activation domains. Both MADS and
MEF2 domains are necessary and sufficient for
dimerization and binding to the DNA sequence
CTA(A/T)4TAG/A. MEF2 domain influences cofactor
interactions (Pollock and Treisman, 1991; Molkentin
and Olson, 1996). Regions: 2-38 aa of the MADS
domain confer DNA binding site specificity; 21-73 aa,
dimerization interface; 59 aa, putative phosphorylation
site.
Identity
Other names: DKFZp686I1536
HGNC (Hugo): MEF2D
Location: 1q22
Note: MEF2D is a member of the family of myocyte
enhancer factor MEF2 that includes MEF2A, MEF2B,
MEF2D, MEF2C.
DNA/RNA
Description
Expression
12 exons.
High level expression in muscles and neurons, at lower
levels in a wide range of cell types (Black and Olson,
1998).
Transcription
5888 bp mRNA, coding sequence: from 391 bp to 1956
bp (NCBI, GenBank NM_005920); alternative splicing
in E3 (3alpha1 and 3alpha2) and beta produces 4
splicing isoforms: alpha1, alpha1beta, alpha2,
alpha2beta (Zhu et al., 2005).
Localisation
Nuclear (Neely et al., 2009).
Function
DNA binding, transcriptional activation. Transmission
of extracellular signals to the genome, control of cell
differentiation, proliferation, morphogenesis, survival
and apoptosis of a wide range of cell types. Important
in immediate-early development in animals. MEF2D
dimers regulate expression of genes involved in
muscle-specific
and/or
growth
factor-related
transcription.
It seems to be transcriptional effector of mitogenic
signaling pathways initiated by mitogen-activated
protein kinases (MAPKs) including p38 and ERK5
(extracellular signal-related kinase 5)/Big MAPK-1,
and also plays critical roles in calcium-regulated
Protein
Note
MEF2D belongs to MEF2 (myocyte enhancer factor 2)like/Type II subfamily of MADS (MCM1, Agamous,
Deficiens, and SRF (serum response factor) box family
of eukaryotic transcriptional regulators).
Description
MEF2D encodes approximately a 521 aa-long protein
(GenBank at NCBI presented 4 isoforms: CRA_a, 521
aa, EAW52952.1; CRA_b, 143 aa, EAW52949.1;
CRA_c, 288 aa, EAW52950.1; CRA_d, 523 aa,
EAW52951.1). It is composed of several domains: the
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
772
MEF2D (myocyte enhancer factor 2D)
Prima V, et al.
A. Localization of TS-2 chromosome 19 breakpoint via FISH. Metaphase FISH was performed using cosmids containing chromosome
19 genomic DNA. Cosmids that hybridize to the der(19) are located centromeric to the chromosome 19 breakpoint (green signal), while
cosmids that hybridize to the der(1) are located telomeric to the chromosome 19 breakpoint (red signal). Split signals on both the der(1)
and der(19) chromosomes indicate that the chromosome 19 breakpoint is located within the region homologous to the cosmid. B.
Alignment of genomic DNA sequences of TS-2 chromosomes. Genomic sequence (accession AY681494) of der(19) aligned with
chromosome 19 (gi: 37552371) and 1 (gi: 37549803) genomic contigs. Non- homologous insert shown in bold uppercase. Genomic
sequence (accession AY681493) of der(1) aligned with chromosome 19 and 1 genomic contigs. (Prima et al., 2007).
signaling pathways that control survival of neurons and
T-cells; induces expression of c-jun, a known
transforming oncogene, and has recently been
identified in murine retroviral mutagenesis studies as a
candidate oncogene involved in the pathogenesis of
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
lymphoid malignancies (Lund et al., 2002; Suzuki et
al., 2002; Han and Prywes, 1995).
Homology
Belongs to MEF2-like/Type II subfamily of MADS
box family of eukaryotic transcriptional regulators. The
773
MEF2D (myocyte enhancer factor 2D)
Prima V, et al.
MADS-box is found so far in a diverse group of
transcription factors from yeast, animals and seed
plants.
acids 1-87 and 105-190. DAZAP1/MEF2D fusion
cDNAs (accession
AY678451) are predicted to encode a chimeric protein
that contains all of the first DAZAP1 RRM and a
truncated portion of the second RRM joined to the
carboxy terminal portion of MEF2D that includes the
second TAD. Reciprocal MEF2D/DAZAP1 fusion
transcripts (accession AY675556) are predicted to
encode a chimera that includes the MEF2D MADSbox, MEF2 domain, and the first TAD joined to the
carboxy terminus of DAZAP1 including a truncated
portion of RRM 2.
DAZAP1 bound strongly to poly(U) and poly(G) at 0.1
M NaCl, whereas DAZAP1/MEF2D bound to the same
homopolymers to a lesser degree; MEF2D/DAZAP1
retains DNA-binding properties of wild type MEF2D;
MEF2D/DAZAP1 is a more potent transcriptional
activator than wild type MEF2D. MEF2D-DAZAP1
was co-immunoprecipitated with wild type MEF2D
from HEK293 cells, suggesting that the wild type and
chimeric MEF2D proteins could form heterodimers
and/or associate with one another in a higher order
protein complex in vivo (Yuki et al., 2004).
Oncogenesis
MEF2D and DAZAP1 fusion proteins were identified
as components of novel pathways that contribute to
human leukemogenesis. Both MEF2D/DAZAP1 and
DAZAP1/MEF2D have oncogenic properties, and coexpression of both fusion proteins is synergistic (Prima
and Hunger, 2007).
MEF2D/DAZAP1 might directly activate transcription
of genes critical for lymphocyte growth and/or survival
such as interleukin-2, a known transcriptional target of
MEF2D in T-cells. Alternatively, MEF2D/DAZAP1
could contribute to leukemogenesis via dysregulated
activation of MAPK-mediated cell proliferation
pathways, analogous to constitutive activation of a
growth factor receptor.
Implicated in
Acute lymphoblastic leukemia (ALL)
Hybrid/Mutated gene
A variant t(1;19)(q23;p13.3) 1048 translocation creates
reciprocal DAZAP1/MEF2D and MEF2D/DAZAP1
fusion genes that are expressed in acute lymphoblastic
leukemia (ALL).
DAZAP1 is expressed most abundantly in the testis and
mapped to 19p13.3. DAZAP1 is fused to MEF2D by
the t(1;19); the genomic breakpoints occur in introns of
MEF2D and DAZAP1 (der(1) (Genbank accession
AY681493) and der(19) (accession AY681494)).
der(19) breakpoint is located within the 1500 kilobases
(kb) of DNA telomeric to E2A. Rearrangments are seen
only in TS-2 (ALL cell line) establishing that the
t(1;19) interrupts the 19p13.3 gene DAZAP1 with the
breakpoint region in approximately the middle of the
gene. There is a 5 base pairs insertion at the site of
genomic fusion on the der(19) that is not derived from
either germline chromosome 1 or 19. Homologous
breakpoints occur on the der(1) chromosome with a
deletion of 97 bp and a 21 bp GC-rich insertion.
MEF2D/DAZAP1 and DAZAP1/MEF2D fusion
transcripts are expressed in-frame in TS-2 cells in
addition to wild-type DAZAP1 and MEF2D transcripts
(Prima et al., 2005).
Abnormal protein
In-frame MEF2D/DAZAP1 and DAZAP1/MEF2D
fusion transcripts are expressed in TS-2 cell line and
define the DNA-, RNA-binding, and transcriptional
regulatory properties of the resultant chimeric proteins.
Native DAZAP1 (NP_061832) includes two identified
RNA recognition motifs (RRM) specified by amino
Structural features of wild type and chimeric MEF2D and DAZAP1 proteins. Predicted functional domains of DAZAP1, MEF2D,
DAZAP1/MEF2D and MEF2D/DAZAP1 proteins. Arrows indicate predicted protein breakpoints. (RRM- RNA recognition motif; MADSDNA binding, protein dimerization domain; MEF2- cofactor interactions domain; TAD- transcriptional activation domain) (Prima et al.,
2007).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
774
MEF2D (myocyte enhancer factor 2D)
Prima V, et al.
Yuki Y, Imoto I, Imaizumi M, Hibi S, Kaneko Y, Amagasa T,
Inazawa J. Identification of a novel fusion gene in a pre-B
acute lymphoblastic leukemia with t(1;19)(q23;p13). Cancer
Sci. 2004 Jun;95(6):503-7
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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8)
This article should be referenced as such:
Prima V, Glushakova LG, Hunger SP. MEF2D (myocyte
enhancer factor 2D). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(8):772-775.
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