SIX1 (sine oculis homeobox homolog 1) (mammalian)

2005-11-01 Heide L Ford , Aaron N Patrick , Marileila Varella-Garcia Affiliation

Depts. of Obstetrics, Gynecology, Biochemistry, Molecular Genetics, University of Colorado Health Sciences Center, Fitzsimons Campus, Mail stop 8309, P.O. Box 6511, Aurora, CO 80045, USA

Identity

HGNC

SIX1

LOCATION

14q23.1

LOCUSID

6495

ALIAS

BOS3,DFNA23,TIP39

FUSION GENES

Show Gene Fusions

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

Proteins

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, Rathkes 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 Wilmstumors, and in rhabdomyosarcoma.

Implicated in

Entity name

Six1 is implicated in a number of cancers including breast cancer, rhabdomyosarcomas, and Wilms 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, wilms 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 Wilms tumors. It has been implicated in both the proliferation and metastasis of tumor cells.

Bibliography

Pubmed ID	Last Year	Title	Authors
15955062	2005	Slc12a2 is a direct target of two closely related homeobox proteins, Six1 and Six4.	Ando Z et al
15254912	2004	Expression of zebrafish six1 during sensory organ development and myogenesis.	Bessarab DA et al
15804569	2005	Six1 is not involved in limb tendon development, but is expressed in limb connective tissue under Shh regulation.	Bonnin MA et al
8617500	1996	Cloning of the human SIX1 gene and its assignment to chromosome 14.	Boucher CA et al
14673635	2004	Genetic determination of nephrogenesis: the Pax/Eya/Six gene network.	Brodbeck S et al
15525662	2004	Six1 promotes a placodal fate within the lateral neurogenic ectoderm by functioning as both a transcriptional activator and repressor.	Brugmann SA et al
15123840	2004	The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1.	Coletta RD et al
14628032	2003	Signal transduction: an eye on organ development.	Epstein JA et al
9770533	1998	Abrogation of the G2 cell cycle checkpoint associated with overexpression of HSIX1: a possible mechanism of breast carcinogenesis.	Ford HL et al
10801845	2000	Cell cycle-regulated phosphorylation of the human SIX1 homeodomain protein.	Ford HL et al
12500905	2002	Six and Eya expression during human somitogenesis and MyoD gene family activation.	Fougerousse F et al
10512683	1999	Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies.	Gallardo ME et al
15653558	2005	New perspectives on eye development and the evolution of eyes and photoreceptors.	Gehring WJ et al
15788460	2005	Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo.	Grifone R et al
15226428	2004	Six1 and Eya1 expression can reprogram adult muscle from the slow-twitch phenotype into the fast-twitch phenotype.	Grifone R et al
10617572	1999	Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and Six1, homologs of genes required for Drosophila eye formation.	Heanue TA et al
12215533	2002	Molecular interaction and synergistic activation of a promoter by Six, Eya, and Dach proteins mediated through CREB binding protein.	Ikeda K et al
10878574	2000	Six family genes--structure and function as transcription factors and their roles in development.	Kawakami K et al
10557309	1999	cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene.	Khan J et al
12668636	2003	Altered myogenesis in Six1-deficient mice.	Laclef C et al
12834866	2003	Thymus, kidney and craniofacial abnormalities in Six 1 deficient mice.	Laclef C et al
12057921	2002	Gene expression in Wilms' tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial transition.	Li CM et al
14628042	2003	Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.	Li X et al
7720577	1995	Homeobox genes and connective tissue patterning.	Oliver G et al
14695375	2004	Six1 controls patterning of the mouse otic vesicle.	Ozaki H et al
10960794	2000	Xenopus Six1 gene is expressed in neurogenic cranial placodes and maintained in the differentiating lateral lines.	Pandur PD et al
15805264	2005	Gene amplification is a mechanism of Six1 overexpression in breast cancer.	Reichenberger KJ et al
10617565	1999	From insect eye to vertebrate muscle: redeployment of a regulatory network.	Relaix F et al
15141091	2004	SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.	Ruf RG et al
9826681	1998	Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site.	Spitz F et al
12783782	2003	Six1 is required for the early organogenesis of mammalian kidney.	Xu PX et al
14704789	2004	Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators.	Yu Y et al
12874121	2003	The role of Six1 in mammalian auditory system development.	Zheng W et al
15496442	2004	Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes.	Zou D et al

Other Information

Locus ID:

NCBI: 6495
MIM: 601205
HGNC: 10887
Ensembl: ENSG00000126778

Variants:

dbSNP: 6495
ClinVar: 6495
TCGA: ENSG00000126778
COSMIC: SIX1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000126778	ENST00000554986	H0YK85
ENSG00000126778	ENST00000645694	Q15475

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Transcriptional misregulation in cancer	KEGG	ko05202
Transcriptional misregulation in cancer	KEGG	hsa05202

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
22286770	2012	The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer.	126
15141091	2004	SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.	119
19726885	2009	The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-beta signaling.	104
15123840	2004	The Six1 homeoprotein stimulates tumorigenesis by reactivation of cyclin A1.	87
20548946	2010	A genome-wide association study of optic disc parameters.	85
25670082	2015	Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors.	75
25670083	2015	Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors.	74
21427129	2011	Common genetic variants associated with open-angle glaucoma.	67
19726883	2009	Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition.	66
20603620	2010	MicroRNA-185 suppresses tumor growth and progression by targeting the Six1 oncogene in human cancers.	59

Citation

Heide L Ford ; Aaron N Patrick ; Marileila Varella-Garcia

SIX1 (sine oculis homeobox homolog 1) (mammalian)

Atlas Genet Cytogenet Oncol Haematol. 2005-11-01

Online version: http://atlasgeneticsoncology.org/gene/42302/six1