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FLASH GENE
Symbol MRTFA contributors: mct - updated : 12-04-2015
HGNC name myocardin-related transcription factor A
HGNC id 14334
Corresponding disease
AMLM7 infantile acute megakaryoblastic leukemia
Location 22q13.1      Physical location : -
Synonym name
  • RBM15/MKL1 fusion
  • basic, SAP and coiled-coil domain
  • megakaryoblastic leukemia (translocation) 1
  • RNA-binding motif protein 15/megakaryoblastic leukemia-1 fusion protein
  • MKL/myocardin-like protein 1
  • megakaryocytic acute leukemia (MAL)
  • Synonym symbol(s) KIAA1438, MAL, AMKL, BSAC, MRTF-A, MKL1
    DNA
    TYPE functioning gene
    STRUCTURE 226.44 kb     15 Exon(s)
    regulatory sequence Promoter
    text structure
  • two putative promoters
  • MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    15 - 4550 98.8 931 - 2014 2458952
  • also called chimeric protein RBM15-MKL1
  • playing a role in chromatin organization through the binding of AT-rich DNA sequences, reconized by the SAF (scarffold attachement factor box)
  • candidate oncoprotein
  • MKL1-elongated derivative of yield, which contain three RPEL motifs
  • 14 - 4400 - 881 - 2014 2458952
  • isoform MKL1met
  • contains two RPEL motifs, shows enhanced nuclear staining compared with the other three isoforms
  • may increase its SRF coactivator function by reducing the
  • suppressive effects of G-actin and increasing its localiza-tion in the nucleus
  • overexpression of MKL1met, increases SRF-mediated transcriptional responses and reduces the number of dendrites
  • 15 - 4560 - 798 - 2014 2458952
    12 - 4138 - 931 - 2014 2458952
  • BSAC isoform, basic, SAP, and coiled-coil domain
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   lowly
    Digestiveesophagus   highly
    Lymphoid/Immunelymph node   highly
    Nervousnerve   highly
    Reproductivefemale systemovary  lowly
    Respiratorylung   lowly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  moderately
    Muscularstriatumskeletal   Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticmegakaryocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text liver, brain
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an N terminal basic SAP (SAF-A/B, Scaffold attachement factor (SAF) box (a 31 aa motif), Acinus, PIAS) with three copies of the RPEL motif (RPXXXEL motifs)
  • a coiled-coil domains
  • an unusually long bipartite nuclear localisation signal (NLS), comprising two basic elements separated by 30 residues, embedded within the RPEL domain, with an actin-sensitive nuclear import signal
  • an N-terminal region required for nuclear localization
  • a C-terminal region mediating transcriptional activity
  • mono polymer heteromer , trimer
    HOMOLOGY
    interspecies homolog to rattus Mkl1 (86.6 pc)
    homolog to murine Mkl1 (85.8 pc)
    Homologene
    FAMILY
    CATEGORY regulatory , DNA associated , transcription factor , protooncogene
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,chromatin/chromosome
    text
  • rapidly shuttles between cytoplasm and nucleus
  • reside mostly in the cytoplasm and translocate to the nucleus in a Rho-dependent manner
  • in muscle cells translocation from the cytoplasm to the nucleus in response to actin polymerization is critical for its function as a transcriptional regulator
  • basic FUNCTION
  • putatively involved in chromatin organization by its SAF box
  • transcriptional activator with antiapoptotic function, which may be involved in the leukemogenesis
  • acting as a cofactor of serum response factor (SRF) and having the potential to modulate SRF-target genes
  • suppressing TNF-induced cell death by inhibiting activation of caspases
  • increase the expression levels of actin cytoskeletal proteins via serum response factor, thereby triggering reorganization of the actin cytoskeleton
  • important mediators of TGF-beta1-induced epithelial-mesenchymal transition
  • may up-regulate antiapoptotic molecules which in turn inhibit caspase activation
  • promotes physiologic maturation of megakaryocytes
  • with MKL2, are co-activators for serum response factor (SRF)
  • promotes differentiation of cardiac fibroblasts to a myofibroblast phenotype and production of stress fibers
  • MKL1-nuclear accumulation following stimulation with serum, actin drugs or acute mechanical stress is prevented within mechanically loaded, anchored matrices at tensional homeostasis
  • controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins
  • SRF and its transcriptional cofactor MKL1 are critical for megakaryocyte maturation and platelet formation
  • MKL1 and MKL2 have both SRF-dependent and SRF-independent activity in megakaryocytopoiesis
  • activator of serum response factor (SRF) transcriptional activity, promoting muscle, neuron, and megakaryocyte differentiation
  • MKL1, MKL2 are required for accurate cell cycle progression and maintenance of genomic stability in fibroblast cells
  • contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction
  • broadly expressed and promotes the expression of genes encoding components of the actin cytoskeleton
  • crucial role for the transcriptional regulator MKL1 and its SAP domain during breast cancer progression
  • MKL1 and PPARG act in a mutually antagonistic manner in the adipocytic differentiation programme
  • MYOCD and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation
  • redundant but essential roles of MKL1, MKL2 in maintenance of cardiac structure and function and as indispensible links in cardiac cytoskeletal gene regulatory networks
  • CELLULAR PROCESS cell life, antiapoptosis
    nucleotide, chromatin organization
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • RHOD/MKL1 signaling pathway is activated during the epithelial-mesenchymal transition, and is a main actor in controlling the cell-specific activity of both transactivation functions of ESR1
  • the current finding of an MKL1/MKL2-regulated pathway in dermal myofibroblast differentiation should accelerate the development of therapeutic strategies directed towards various fibrotic diseases including keloid formation
  • a component
  • forming a ternary complex with SRF on DNA
  • INTERACTION
    DNA
  • binding to AT-rich sequences
  • using the canonical single or multiple CArG boxes DNA sequence
  • RNA
    small molecule
    protein
  • interacting with MKL2
  • binding to monomeric actin
  • RBM15-MKL1 fusion gene is a constitutive activator of SRF and target gene expression, and deregulated activator of serum response factor-dependent gene expression contributes to the malignancy)
  • co-activator for serum response factor (SRF) (with SRF are required for cytoskeletal dynamics and experimental metastasis)
  • bind G-actin through their N-terminal RPEL domains
  • is a Rho signalling-responsive co-activator of serum response factor (SRF)
  • nuclear-localized MKL1 activates the transcription of SRF target genes
  • TMSB4X is an important MKL1 regulator that controls the G-actin-MKL1 interaction
  • required for TGFB1–induced contractile gene expression and stress fiber formation
  • MKL2 plays a redundant role to that of MKL1 either in fibroblasts or in keratinocytes
  • MICAL2 induces redox-dependent depolymerization of nuclear actin, which decreases nuclear G-actin and increases MKL1 in the nucleus
  • SRF utilizes MKL1/2 to fulfill steady state cellular functions, including cytoskeletal organization, and utilizes ELK4 to facilitate acute responses to external infection
  • critical link between protein arginylation and MRTFA activity and ATE1 is upstream of MRTFA
  • SRF regulates craniofacial development through selective recruitment of MKL1 cofactors by PDGFA signaling
  • TGFB1I1 is required for myofibroblast differentiation by regulating mechanically dependent MKL1 nuclear accumulation
  • cell & other
  • binds to G-actin through RPXXXEL (RPEL) motifs
  • REGULATION
    Other serum stimulation effectively blocked nuclear export
    tissuetension regulates MKL1/SRF activity through cofilin-mediated modulation of actin dynamics
    ASSOCIATED DISORDERS
    corresponding disease(s) AMLM7
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral fusion translocation   protein chimeric
    5' - OOT - MEAL - 3' in translocation t (1;22) (p13;q13) in acute megakaryocytic leukemia
    tumoral fusion      
    RBM15-MKL1 fusion protein is the result of the recurrent translocation t(1;22) in acute megakaryocytic leukemia in infants
    Susceptibility to coronary artery disease (CAD)
    Variant & Polymorphism SNP promoter SNP of MKL1, -184C > T, was found associated with CAD
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    miscelleaneousvascular 
    could thus be a novel therapeutic target for the treatment of vascular diseases
    ANIMAL & CELL MODELS
  • deletion of Mrtf-A in mice attenuates myofibroblast responses following cardiac injury and reduces cardiac fibrosis and scarring
  • defects observed in Mrtf-A/B null mice ranged from reduced cardiac contractility and adult onset heart failure to neonatal lethality accompanied by sarcomere disarray