MEF2D (myocyte enhancer factor 2D)

2009-10-01   Victor Prima , Lyudmyla G Glushakova , Stephen P Hunger 

University of Florida College of Medicine, Gainesville, FL 32610, USA (VP, LGG); Childrens Hospital, the Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA (SPH)

Identity

HGNC
LOCATION
1q22
LOCUSID
ALIAS
-
FUSION GENES

DNA/RNA

Description

12 exons.

Transcription

5888bp mRNA, coding sequence: from 391bp to 1956bp (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).

Proteins

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 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.

Expression

High level expression in muscles and neurons, at lower levels in a wide range of cell types (Black and Olson, 1998).

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 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 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 MADS-box is found so far in a diverse group of transcription factors from yeast, animals and seed plants.

Implicated in

Entity name
Acute lymphoblastic leukemia (ALL)
Hybrid 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).
Atlas Image
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).
Fusion 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 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 MADS-box, 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).
Atlas Image
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; MADS- DNA binding, protein dimerization domain; MEF2- cofactor interactions domain; TAD- transcriptional activation domain). (Prima et al., 2007).
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 co-expression 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.

Bibliography

Pubmed IDLast YearTitleAuthors
98917821998Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins.Black BL et al
77607901995Regulatory role of MEF2D in serum induction of the c-jun promoter.Han TH et al
121853672002Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice.Lund AH et al
87903351996Combinatorial control of muscle development by basic helix-loop-helix and MADS-box transcription factors.Molkentin JD et al
193620762009Localization of myocyte enhancer factor 2 in the rodent forebrain: regionally-specific cytoplasmic expression of MEF2A.Neely MD et al
17482871991Human SRF-related proteins: DNA-binding properties and potential regulatory targets.Pollock R et al
157443502005Cloning and functional characterization of MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins created by a variant t(1;19)(q23;p13.3) in acute lymphoblastic leukemia.Prima V et al
178987852007Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia.Prima V et al
121853652002New genes involved in cancer identified by retroviral tagging.Suzuki T et al
151824312004Identification of a novel fusion gene in a pre-B acute lymphoblastic leukemia with t(1;19)(q23;p13).Yuki Y et al
158341312005Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain.Zhu B et al

Other Information

Locus ID:

NCBI: 4209
MIM: 600663
HGNC: 6997
Ensembl: ENSG00000116604

Variants:

dbSNP: 4209
ClinVar: 4209
TCGA: ENSG00000116604
COSMIC: MEF2D

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000116604ENST00000348159Q14814
ENSG00000116604ENST00000360595Q14814
ENSG00000116604ENST00000368240Q05BX2
ENSG00000116604ENST00000464356Q14814
ENSG00000116604ENST00000475587Q05BX2
ENSG00000116604ENST00000489057A0A0G2JLL8

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Mitochondrial biogenesisREACTOMER-HSA-1592230
Transcriptional activation of mitochondrial biogenesisREACTOMER-HSA-2151201
Circadian ClockREACTOMER-HSA-400253
Developmental BiologyREACTOMER-HSA-1266738
MyogenesisREACTOMER-HSA-525793
CDO in myogenesisREACTOMER-HSA-375170
Apelin signaling pathwayKEGGhsa04371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
191192332009Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy.114
161666282005Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications.107
206826872010Common variants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program.88
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
171589262007Histone deacetylase 3 interacts with and deacetylates myocyte enhancer factor 2.84
213938612011Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients.58
158341312005Alternative pre-mRNA splicing governs expression of a conserved acidic transactivation domain in myocyte enhancer factor 2 factors of striated muscle and brain.33
186604892008Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.26
254728772015Oleanolic acid suppresses the proliferation of lung carcinoma cells by miR-122/Cyclin G1/MEF2D axis.24
273645592016MEF2D Transduces Microenvironment Stimuli to ZEB1 to Promote Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.23

Citation

Victor Prima ; Lyudmyla G Glushakova ; Stephen P Hunger

MEF2D (myocyte enhancer factor 2D)

Atlas Genet Cytogenet Oncol Haematol. 2009-10-01

Online version: http://atlasgeneticsoncology.org/gene/43636/mef2d