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Symbol SIX1 contributors: mct/npt/pgu - updated : 22-01-2014
HGNC name SIX homeobox 1
HGNC id 10887
  • six domains and a helix-turn-helix DNA (homeo) binding domain
  • conjugated PhosphoP
    interspecies homolog to Drosophila sine oculis homeobox SIX1
  • six/sine oculis homeobox family
  • CATEGORY motor/contractile
    SUBCELLULAR LOCALIZATION     intracellular
    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
  • EYA1 and SIX1 as key components of the SHH transcriptional network in normal development and in oncogenesis
    a component
  • EYA2-SIX1 complex binds to and enhances the expression of MTOR in a synergistic manner
    DNA DNA binding
    small molecule
  • 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
  • SKI is necessary for muscle terminal differentiation and it exerts this role, at least in part, through its association with SIX1 and EYA3 to regulate the MYOG transcription
  • neural crest specifier activity of GBX2 is dependent on the interaction with ZIC1 and the inhibition of preplacodal genes such as SIX1
  • EYA3 and its partner SIX1 synergistically activate TSHB expression (TSHB plays a key role in the pathway that regulates vertebrate photoperiodism)
  • 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
  • HDAC5 promoted hepatocellular carcinoma cell proliferation through up-regulation of SIX1 expression
  • catalytically active phosphatase EYA1 cooperates with the DNA-binding protein SIX1 to promote gene induction in response to SHH and EYA1/SIX1 together regulate GLI transcriptional activators
  • cell & other
    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
    Variant & Polymorphism
    Candidate gene
    Therapy target
    inhibition of SIX1 promotes apoptosis, suppresses proliferation, and migration of osteosarcoma cells
  • 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