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SIX1 (sine oculis homeobox homolog 1) (mammalian)

Identity

Other namesHSIX1 (human SIX1)
Sine oculis (Drosophila homolog)
HGNC (Hugo) SIX1
Location 14q23
Location_base_pair Starts at 60181170 and ends at 60185908 bp from pter ( according to hg18-Mar_2006)  [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)ENSG00000126778 [Gene_View]  SIX1 [Vega]
AceView (NCBI)SIX1
Genatlas (Paris)SIX1
euGene (Indiana)6495
SOURCE (Stanford)NM_005982
Genomic and cartography
GoldenPath (UCSC)SIX1  -  14q23   chr14:60181170-60185908 -  14q23.1   [Description]    (hg18-Mar_2006)
EnsemblSIX1 - 14q23.1 [CytoView]
Mapping of homologs : NCBISIX1 [Mapview]
OMIM601205   605192   608389   
Gene and transcription
Gene : Genbank (Entrez)BC008874 BT007083 X91868
Reference sequence (RefSeq transcript) :SRSNM_005982
Reference transcript : EntrezNM_005982
RefSeq genomic : SRSAC_000057 AC_000146 NC_000014 NG_008231 NT_026437 NW_001838111 NW_925561
RefSeq genomic : EntrezAC_000057 AC_000146 NC_000014 NG_008231 NT_026437 NW_001838111 NW_925561
Consensus coding sequences : CCDS NCBISIX1
Cluster EST : UnigeneHs.716658 [ SRS ] Hs.716658 [ NCBI ]
Alternative Splicing : Fast-db (Paris)812
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ15475 (SRS) Q15475 (Expasy) Q15475 (Uniprot)
With graphics : InterProQ15475
Splice isoforms : VarSplice FASTAQ15475(VarSplice FASTA)
Domaine pattern : Prosite (SRS)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domain pattern : Prosite (Expaxy)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (SRS)Homeobox    Homeodomain-rel    HTH_lambrepressr   
Domains : Interpro (EBI)Homeobox    Homeodomain-rel    HTH_lambrepressr   
Related proteins : CluSTrQ15475
Domain families : Pfam SRSHomeobox (PF00046)   
Domain families : Pfam SangerHomeobox (PF00046)   
Domain families : Pfam NCBIpfam00046   
Domain families : Smart EMBLHOX (SM00389)
Domain structure : Prodom (Prabi Lyon)Homeobox (PD000010)   
Blocks (Seattle)Q15475
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
HPRD03125
Protein Interaction databases
DIP (DOE-UCLA)Q15475
IntAct (EBI)Q15475
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBISIX1
SNP : GeneSNP UtahSIX1
SNP : HGBaseSIX1
Genetic variants : HAPMAPSIX1
Mutations and Diseases : HGMDSIX1
Hereditary diseases : OMIM601205    605192    608389   
Hereditary diseases : GENETests601205    605192    608389   
Diseases : Genetic AssociationSIX1
General knowledge
Homologs : HomoloGeneSIX1
Homology/Alignments : Family Browser UCSCSIX1
Phylogenetic Trees/Animal Genes : TreeFamSIX1
Chemical/Protein Interactions : CTD6495
Keywords Ontology : AmiGOureteric bud branching  induction of an organ  transcription factor activity  protein binding  nucleus  transcription factor complex  nucleolus  cytoplasm  regulation of transcription, DNA-dependent  pattern specification process  muscle development  skeletal muscle development  sensory perception of sound  epithelial cell differentiation  thyroid gland development  inner ear morphogenesis  sequence-specific DNA binding  regulation of neuron differentiation  thymus development  embryonic skeletal system morphogenesis  myoblast migration  
Keywords Ontology : EGO-EBIureteric bud branching  induction of an organ  transcription factor activity  protein binding  nucleus  transcription factor complex  nucleolus  cytoplasm  regulation of transcription, DNA-dependent  pattern specification process  muscle development  skeletal muscle development  sensory perception of sound  epithelial cell differentiation  thyroid gland development  inner ear morphogenesis  sequence-specific DNA binding  regulation of neuron differentiation  thymus development  embryonic skeletal system morphogenesis  myoblast migration  
Pathways : BIOCARTA
Pathways : KEGG
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
Probes : ImagenesSIX1 Related clones (RZPD - Berlin)
Literature
PubMed31 Pubmed reference(s) in Entrez
PubGeneSIX1

Bibliography

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The Human Six family of homeobox genes.
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Gene expression in Wilms' tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial transition.
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Six and Eya expression during human somitogenesis and MyoD gene family activation.
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Six1 is required for the early organogenesis of mammalian kidney.
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The role of Six1 in mammalian auditory system development.
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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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Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes.
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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.
Ozaki H, Nakamura K, Funahashi J, Ikeda K, Yamada G, Tokano H, Okamura HO, Kitamura K, Muto S, Kotaki H, Sudo K, Horai R, Iwakura Y, Kawakami K
Development (Cambridge, England). 2004 ; 131 (3) : 551-562.
PMID 14695375
 
SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.
Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper MJ, Raymond RM Jr, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C, Hildebrandt F
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Six1 promotes a placodal fate within the lateral neurogenic ectoderm by functioning as both a transcriptional activator and repressor.
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The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1.
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Gene amplification is a mechanism of Six1 overexpression in breast cancer.
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New perspectives on eye development and the evolution of eyes and photoreceptors.
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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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Development (Cambridge, England). 2005 ; 132 (9) : 2235-2249.
PMID 15788460
 
Six1 is not involved in limb tendon development, but is expressed in limb connective tissue under Shh regulation.
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Mechanisms of development. 2005 ; 122 (4) : 573-585.
PMID 15804569
 
Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4.
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PMID 15955062
 
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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

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