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SIX1 (sine oculis homeobox homolog 1) (mammalian)

Identity

Other namesHSIX1 (human SIX1)
Sine oculis (Drosophila homolog)
HGNC (Hugo) SIX1
LocusID (NCBI) 6495
Location 14q23.1
Location_base_pair Starts at 61111417 and ends at 61116155 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

 
  View of the SIX1 gene which is composed of 2 exons that are 833 and 543 bps respectively, and a single 2,052 bp intron. Start and stop codon positions are shown.
Description The gene is composed of 2 exons and one intron and can be found on chromosome 14 at location 60,182,506-60,185,933.
Transcription The transcript length is 1,376 base pairs and the start of the transcript is located in Contig AL049874.3.1.193047. The transcript can be detected in a variety of tissues during mouse development (see below for protein expression) and this has also been confirmed at the protein level (using reporter genes). The transcript is further detected throughout normal mouse mammary gland development with levels being the highest in the embryonic mammary gland and decreasing as the mammary gland differentiates in pregnancy and lactation. In the adult human, it is detected in skeletal muscle, pituitary gland, salivary gland, kidney, lung, and trachea.
Pseudogene No

Protein

 
  View of the Six1 protein (total length 284 amino acids) that contains an N-terminal 115 amino acid Six domain (SD), and a 60 amino acid six-type homeodomain (HD). The SD is important for the interaction of Six1 with cofactors and also contributes to DNA binding along with the homeodomain.
Description Six1 belongs to the Six family of homeoproteins. Amino acids: 284. Predicted Molecular Weight: 32210 Dalton. It exists as a phosphoprotein and is hyperphosphorylated in mitosis.
Expression During mouse development, Six1 is expressed in otic vesicles, nasal placodes, branchial arches, Rathke¹s pouch, dorsal root ganglion, proximal cranial ganglia, somites, cranial mesenchyme, nephrogenic cords, and limb mesenchyme. Six1 expression in muscles is present throughout myogenesis and into adulthood.
Localisation Nuclear
Function Six1 is a transcription factor that is known to play a role in the proliferation and survival of precursor cells during normal development in numerous tissues including, amongst others, the kidney, inner ear, and muscle. It is also demonstrated to play a role in the proliferation of cancer cells and in cancer metastasis. It is known to activate several target genes, including cyclin A1, c-MYC, GDNF, and SLC12A2.

Mutations

Germinal Germline mutations of SIX1 are observed in branchio-oto-renal sydrome, an autosomal dominant developmental disorder that is characterized by kidney and urinary tract malformations and hearing loss. The three SIX1 mutations identified to date all interfere with the ability of the Six1 protein to interact with its Eya1 cofactor, and two of the identified mutations additionally affect Six1-DNA binding.
Somatic The SIX1 gene is amplified in about 5% of breast cancers (infiltrating ductal carcinomas). Overexpression of Six1 has been found in breast cancer, in Wilms¹tumors, and in rhabdomyosarcoma.

Implicated in

Entity Six1 is implicated in a number of cancers including breast cancer, rhabdomyosarcomas, and Wilms¹ tumors. It has also been implicated in branchio-oto-renal syndrome.
Note Six1 is overexpressed in approximately 50% of primary breast cancers and 90% of metastatic lesions. Its overexpression in breast cancer has been linked to increased proliferation of breast cancer cells. Six1 is also a critical mediator of metastasis in a mouse rhabdomyosarcoma model.
Disease breast cancer, wilms¹ tumor, rhabdomyosarcoma, branchio-oto-renal syndrome,
Cytogenetics The SIX1 gene is amplified in human breast cancer
 
Idiogram of chromosome 14 (A) showing location of the SIX1 gene at 14q23 (clone RP11-1042B17, labeled in SpectrumRed). Clone RPMI-324B11 (labeled in SpectrumGreen) mapped at 14q11.2 was used as control. Metaphase spread (B) and interphase nuclei (C) of the non-malignant, immortalized MCF10A cell line showing two normal copies of chromosome 14 with signals generated by the SIX1 and control FISH probes. Metaphase spread of the mammary carcinoma cell line, 21MT2 (D), showing a normal copy of chromosome 14 with SIX1 (red) and control probe (green), two derivative chromosomes carrying only the SIX1 or the SIX1 and control signals and a copy of the derivative 14 chromosome with SIX1 gene amplification. Interphase nuclei from 21MT2 cells with multiple copies of red and green signals, including a cluster of SIX1 signals representing gene amplification (E).
Oncogenesis SIX1 is overexpressed in several tumor types, including breast cancer, rhabdomyosarcomas, and Wilms¹ tumors. It has been implicated in both the proliferation and metastasis of tumor cells.
  

External links

Nomenclature
HGNC (Hugo)SIX1   10887
Entrez_Gene (NCBI)SIX1  6495  SIX homeobox 1
Cards
AtlasSIX1ID42302ch14q23
GeneCards (Weizmann)SIX1
Ensembl (Hinxton) [Gene_View]  chr14:61111417-61116155 [Contig_View]  SIX1 [Vega]
AceView (NCBI)SIX1
Genatlas (Paris)SIX1
SOURCE (Stanford)NM_005982
Genomic and cartography
GoldenPath (UCSC)SIX1  -  14q23.1   chr14:61111417-61116155 -  14q23.1   [Description]    (hg19-Feb_2009)
EnsemblSIX1 - 14q23.1 [CytoView]
Mapping of homologs : NCBISIX1 [Mapview]
OMIM601205   605192   608389   
Gene and transcription
Genbank (Entrez)BC008874 BT007083 X91868
RefSeq transcript (SRS)NM_005982
RefSeq transcript (Entrez)NM_005982
RefSeq genomic (SRS)AC_000146 NC_000014 NC_018925 NG_008231 NT_026437 NW_001838111 NW_004929393
RefSeq genomic (Entrez)AC_000146 NC_000014 NC_018925 NG_008231 NT_026437 NW_001838111 NW_004929393
Consensus coding sequences : CCDS (NCBI)SIX1
Cluster EST : UnigeneHs.633506 [ SRS ] Hs.633506 [ NCBI ]
CGAP (NCI)Hs.633506
Alternative Splicing : Fast-db (Paris)GSHG0009408
Gene ExpressionSIX1 [ NCBI-GEO ]   SIX1 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15475 (SRS) Q15475 (Uniprot)
NextProtQ15475  [Medical]
With graphics : InterProQ15475
Splice isoforms : SwissVarQ15475(Swissvar)
Domaine pattern : Prosite (SRS)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domaine pattern : Prosite (Expaxy)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (SRS)Homeobox_CS    Homeobox_dom    Homeodomain-like   
Domains : Interpro (EBI)Homeobox_CS    Homeobox_dom    Homeodomain-like   
Related proteins : CluSTrQ15475
Domain families : Pfam (SRS)Homeobox (PF00046)   
Domain families : Pfam (Sanger)Homeobox (PF00046)   
Domain families : Pfam (NCBI)pfam00046   
Domain families : Smart (EMBL)HOX (SM00389)  
DMDM6495
Blocks (Seattle)Q15475
PDB (SRS)4EGC   
PDB (PDBSum)4EGC   
PDB (IMB)4EGC   
PDB (RSDB)4EGC   
HPRD03125
IPIIPI00017506   IPI01025253   
Protein Interaction databases
DIP (DOE-UCLA)Q15475
IntAct (EBI)Q15475
REACTOMESIX1
Protein Interaction Database6495
BioGRIDSIX1
InParanoidQ15475
Interologous Interaction database Q15475
IntegromeDBSIX1
Gene fusion - rearrangments
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)SIX1
SNP (GeneSNP Utah)SIX1
SNP : HGBaseSIX1
Genetic variants : HAPMAPSIX1
Somatic Mutations in Cancer : COSMICSIX1 
CONAN: Copy Number AnalysisSIX1 
Mutations and Diseases : HGMDSIX1
OMIM601205    605192    608389   
GENETests601205    605192    608389   
Disease Genetic AssociationSIX1
Huge Navigator SIX1 [HugePedia]  SIX1 [HugeCancerGEM]
Genomic VariantsSIX1  SIX1 [DGVbeta]
ClinVarSIX1
snp3D : Map Gene to Disease6495
General knowledge
Homologs : HomoloGeneSIX1
Homology/Alignments : Family Browser (UCSC)SIX1
Phylogenetic Trees/Animal Genes : TreeFamSIX1
Chemical/Protein Interactions : CTD6495
Chemical/Pharm GKB GenePA35787
Clinical trialSIX1
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  ureteric bud development  branching involved in ureteric bud morphogenesis  organ induction  kidney development  outflow tract morphogenesis  DNA binding  chromatin binding  sequence-specific DNA binding transcription factor activity  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  transcription factor complex  nucleolus  cytoplasm  transcription, DNA-templated  regulation of transcription, DNA-dependent  apoptotic process  pattern specification process  skeletal muscle tissue development  sensory perception of sound  regulation of synaptic growth at neuromuscular junction  facial nerve morphogenesis  epithelial cell differentiation  thyroid gland development  regulation of protein localization  protein localization to nucleus  aorta morphogenesis  inner ear morphogenesis  middle ear morphogenesis  negative regulation of neuron apoptotic process  sequence-specific DNA binding  transcription regulatory region DNA binding  regulation of neuron differentiation  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  thymus development  neuron fate specification  generation of neurons  embryonic cranial skeleton morphogenesis  embryonic skeletal system morphogenesis  inner ear development  myoblast migration  pharyngeal system development  otic vesicle development  metanephric mesenchyme development  regulation of branch elongation involved in ureteric bud branching  positive regulation of ureteric bud formation  mesonephric tubule formation  ureter smooth muscle cell differentiation  positive regulation of secondary heart field cardioblast proliferation  cochlea morphogenesis  positive regulation of branching involved in ureteric bud morphogenesis  negative regulation of branching involved in ureteric bud morphogenesis  positive regulation of mesenchymal cell proliferation involved in ureter development  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  ureteric bud development  branching involved in ureteric bud morphogenesis  organ induction  kidney development  outflow tract morphogenesis  DNA binding  chromatin binding  sequence-specific DNA binding transcription factor activity  sequence-specific DNA binding transcription factor activity  protein binding  nucleus  transcription factor complex  nucleolus  cytoplasm  transcription, DNA-templated  regulation of transcription, DNA-dependent  apoptotic process  pattern specification process  skeletal muscle tissue development  sensory perception of sound  regulation of synaptic growth at neuromuscular junction  facial nerve morphogenesis  epithelial cell differentiation  thyroid gland development  regulation of protein localization  protein localization to nucleus  aorta morphogenesis  inner ear morphogenesis  middle ear morphogenesis  negative regulation of neuron apoptotic process  sequence-specific DNA binding  transcription regulatory region DNA binding  regulation of neuron differentiation  positive regulation of transcription, DNA-dependent  positive regulation of transcription from RNA polymerase II promoter  thymus development  neuron fate specification  generation of neurons  embryonic cranial skeleton morphogenesis  embryonic skeletal system morphogenesis  inner ear development  myoblast migration  pharyngeal system development  otic vesicle development  metanephric mesenchyme development  regulation of branch elongation involved in ureteric bud branching  positive regulation of ureteric bud formation  mesonephric tubule formation  ureter smooth muscle cell differentiation  positive regulation of secondary heart field cardioblast proliferation  cochlea morphogenesis  positive regulation of branching involved in ureteric bud morphogenesis  negative regulation of branching involved in ureteric bud morphogenesis  positive regulation of mesenchymal cell proliferation involved in ureter development  
Other databases
Probes
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=181266&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206381&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206383&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206384&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206385&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206394&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206414&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206415&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206416&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206417&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206418&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206419&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1206420&term=human+Six1
Probehttp://www.ncbi.nlm.nih.gov/genome/probe/reports/probereport.cgi?uid=1217428&term=human+Six1
Litterature
PubMed62 Pubmed reference(s) in Entrez
PubGeneSIX1
iHOPSIX1

Bibliography

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Six1 is required for the early organogenesis of mammalian kidney.
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Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators.
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Genetic determination of nephrogenesis: the Pax/Eya/Six gene network.
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Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype.
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Six1 controls patterning of the mouse otic vesicle.
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SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.
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Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo.
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Contributor(s)

Written11-2005Heide L Ford, Aaron N Patrick, Marileila Varella-Garcia
Depts. of Obstetrics and Gynecology and Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Fitzsimons Campus, Mail stop 8309, P.O. Box 6511, Aurora, CO 80045, USA

Citation

This paper should be referenced as such :
Ford HL, Patrick AN, Varella-Garcia M . SIX1 (sine oculis homeobox homolog 1) (mammalian). Atlas Genet Cytogenet Oncol Haematol. November 2005 .
URL : http://AtlasGeneticsOncology.org/Genes/SIX1ID42302ch14q23.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38295/1/11-2005-SIX1ID42302ch14q23.pdf   [ Bibliographic record ]

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