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FLASH GENE
Symbol SIX1 contributors: mct/npt/pgu - updated : 22-01-2014
HGNC name SIX homeobox 1
HGNC id 10887
Corresponding disease
BOR3 branchio-oto-renal syndrome 3
BOS3 branchio-otic syndrome 3
DFNA23 neurosensory deafness 23
Location 14q23.1      Physical location : 61.111.417 - 61.116.155
Synonym name sine oculis homeobox homolog 1 (Drosophila)
Synonym symbol(s) TIP39
DNA
TYPE functioning gene
STRUCTURE 4.74 kb     2 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
Physical map
DACT1 14q22.3 dapper homolog 1, antagonist of beta-catenin (xenopus) LOC387991 14 similar to ribosomal protein L31 LOC390482 14 similar to Aldo-keto reductase family 1, member B1 PPIAP5 14 peptidylprolyl isomerase A (cyclophilin A) pseudogene 5 DAAM1 14q22.3 dishevelled associated activator of morphogenesis 1 GPR135 14q23.1 G protein-coupled receptor 135 FLJ25436 14q23.1 hypothetical protein FLJ25436 C14orf100 14q22.3 chromosome 14 open reading frame 100 RTN1 14q21-q22 reticulon 1 FLJ46156 14q23.1 FLJ46156 protein C14orf135 14q23.1 chromosome 14 open reading frame 135 DHRS7 14q23.1 dehydrogenase/reductase (SDR family) member 7 PSMA3P 14 proteasome (prosome, macropain) subunit, alpha type, 3 pseudogene PPM1A 14q22.3-q23.1 protein phosphatase 1A (formerly 2C), magnesium-dependent, alpha isoform RBM8B 14q22.1-q22.3 RNA binding motif protein 8B pseudogene C14orf39 14q23.1 chromosome 14 open reading frame 39 LOC390483 14 similar to sal-like 4 SIX6 14q22.3-q23 sine oculis homeobox homolog 6 (Drosophila) LOC387992 14 LOC387992 SIX1 14q22-q23 sine oculis homeobox homolog 1 (Drosophila) SIX4 14q23 sine oculis homeobox homolog 4 (Drosophila) MNAT1 14q23 menage a trois 1 (CAK assembly factor) MAD2L1P 14 MAD2 mitotic arrest deficient-like 1 (yeast) pseudogene SRMP2 14 spermidine synthase pseudogene 2 SLC38A6 14q23.1 solute carrier family 38, member 6 LOC161291 14q23.1 hypothetical protein LOC161291 PRKCH 14q22-q23 protein kinase C, eta HIF1A 14q21-q24 hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) SNAPC1 14q22 small nuclear RNA activating complex, polypeptide 1, 43kDa LOC122867 14q23.1 similar to cytochrome c oxidase subunit IV (COXIV) pseudogene (E.C. 1.9.3.1) MOCS3P 14 molybdenum cofactor synthesis 3 pseudogene SYT14L 14q23.2 synaptotagmin XIV-like LOC390484 14 similar to ATP synthase alpha subunit KCNH5 14q23.1 potassium voltage-gated channel, subfamily H (eag-related), member 5
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
2 - 2687 - 284 - 2000 10801845
EXPRESSION
Type restricted
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Lymphoid/Immunethymus    
Respiratorylung    
Urinarybladder    
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Muscularsmooth   
Muscularstriatumskeletal   Mus musculus
cell lineage
cell lines
fluid/secretion
at STAGE
physiological period fetal, pregnancy
Text during development in limb tendons
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • six domains and a helix-turn-helix DNA (homeo) binding domain
  • conjugated PhosphoP
    HOMOLOGY
    interspecies homolog to Drosophila sine oculis homeobox SIX1
    Homologene
    FAMILY
  • six/sine oculis homeobox family
  • CATEGORY motor/contractile
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleolus
    basic FUNCTION
  • may be involved in limb tendon and ligament development
  • required for the primary myogenesis
  • nuclear phosphoprotein, hyperphosphorylated by CK2 and implicated in cancer and in cell cycle control
  • SIX1 and SIX4 may act synergistically to mediate olfactory placode specification and patterning through FGF and BMP signaling pathways
  • essential function in the MM (metanephric mesenchyme) as an upstream regulator of GREM1 in initiating branching morphogenesis
  • plays important roles in proliferation, differentiation and survival of precursor cells of different organs
  • critical coordinator of SHH-FGF10 signaling during embryonic lung development, and critical for coordination of proper lung epithelial, mesenchymal and vascular development
  • critical regulator of embryonic development that requires interaction with the EYA family of proteins
  • SIX1 and SIX4 are essential global regulators of muscle gene expression, as well as a central switch to drive the skeletal muscle fast phenotype during fetal development
  • SIX1 and SIX4 function synergistically to form gustatory papillae during development of the tongue
  • upon loss of EZH2, SIX1 might activate transcription of a subset of skeletal muscle genes in cardiomyocytes, contributing to instability of cardiac gene expression
  • EZH2 modulates a feed-forward pathway that represses fetal gene expression and is reinforced by repression of SIX1
  • EYA1 and SIX1 are key transcription factors in initiating the neuronal developmental program, probably by recruiting and interacting with the SWI/SNF chromatin-remodeling complex to specifically mediate NEUROG1 and NEUROD1 transcription
  • SIX1 homeoproteins act as a rheostat system to ensure proper regeneration of the tissue and replenishment of the stem cell pool during the events that follow skeletal muscle trauma
  • may play an important role in adult myogenesis, in addition to its role in embryonic muscle formation
  • SIX1 and SIX4 are required for male gonadal differentiation
  • combinatorial expression of SIX1, SIX2, and SIX4 is required for the molecular programs governing craniofacial and cerebral development
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    PATHWAY
    metabolism
    signaling
    a component
  • EYA2-SIX1 complex binds to and enhances the expression of MTOR in a synergistic manner
  • INTERACTION
    DNA DNA binding
    RNA
    small molecule
    protein
  • EYA1 and DACH1, mediated by CREBBP(regulating precursor cell proliferation and survival during oganogenesis)
  • target of CK2 in G(2)/M checkpoint control and both molecules participate in the same pathway whose dysregulation leads to cancer
  • SIX1 and SIX4 regulate SLC12A2
  • SIX4 cooperates with SIX1 in the metanephric mesenchyme to regulate the level of GDNF expression
  • neural crest specifier activity of GBX2 is dependent on the interaction with ZIC1 and the inhibition of preplacodal genes such as SIX1
  • SIX1 and TBX18 genetically interact to synergistically regulate smooth muscle cells development and ureter function
  • is dependent on EYA2 to mediate numerous pro-metastatic characteristics
  • EYA2 in a physical complex with SIX1 plays a critical role in physiological hypertrophy of heart
  • EZH2-mediated repression of SIX1 in differentiating cardiac progenitors is essential for stable gene expression and homeostasis in the postnatal heart
  • transcription factor essential for embryonic myogenesis, also regulating MYOD1 expression in muscle progenitor cells
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) BOS3 , DFNA23 , BOR3
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in metastatic rhabdomyosarcoma
    constitutional     --over  
    can attenuate a DNA damage-induced G(2) cell cycle checkpoint
    tumoral     --low  
    in 44 p100 of primary breast cancers and 90 p100 of metastatic lesions
    tumoral     --over  
    in osteosarcoma cell lines compared to human osteoblastic cell line
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerbone 
    inhibition of SIX1 promotes apoptosis, suppresses proliferation, and migration of osteosarcoma cells
    ANIMAL & CELL MODELS
  • Six1-deficient mice lack kidneys, but form ureters
  • Six1(-/-) embryos and newborn mice exhibit mesenchymal overproliferation, decreased Fgf10 expression and severe defects in the smooth muscle component of the bronchi and major pulmonary vessels