SIX1 (sine oculis homeobox homolog 1) (mammalian)

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

LOCATION

14q23.1

LOCUSID

ALIAS

BOS3,DFNA23,TIP39

FUSION GENES

Show Gene Fusions

DNA/RNA

Atlas Image

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

Proteins

Atlas Image

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

Atlas Image

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

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)

0

5

10

15

20

25

30

35

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/case-report-explorer/js/web-card-gene.js