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SOX4 (SRY (sex determining region Y)-box 4)

Written2009-01David L Satinover, Chris A Moskaluk
Dept. of Pathology, Dept. of Biochemistry, Molecular Genetics P.O. Box 800214 University of Virginia Health System Charlottesville, VA 22908, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesSRY (sex determining region Y)-box 4
SRY box 4
Other aliasEVI16
OTTHUMP00000039358
HGNC (Hugo) SOX4
LocusID (NCBI) 6659
Atlas_Id 42358
Location 6p22.3  [Link to chromosome band 6p22]
Location_base_pair Starts at 21593741 and ends at 21598618 bp from pter ( according to hg19-Feb_2009)  [Mapping SOX4.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ATP1A3 (19q13.2) / SOX4 (6p22.3)C2CD3 (11q13.4) / SOX4 (6p22.3)SOX4 (6p22.3) / C2CD3 (11q13.4)
SOX4 (6p22.3) / GRIP1 (12q14.3)SOX4 (6p22.3) / PSMD14 (2q24.2)SOX4 (6p22.3) / SOX4 (6p22.3)
SOX4 (6p22.3) / TNNC1 (3p21.1)

DNA/RNA

Description This intronless gene encompasses 4789 base pairs.
Transcription The mRNA transcript is 4789 base pairs.

Protein

Description The mRNA encodes a 47.3 kDa protein consisting of 474 amino acids.
Expression SOX4 appears to be fairly ubiquitously expressed at low levels in most adult tissues, with high levels found mostly in T lymphocytes. Its expression is up-regulated in many cancer types relative to benign tissue of origin (Rhodes et al., 2004).
Localisation Nucleus.
Function SOX4 is a member of the class I SRY-related HMG-box family of transcription factors. It has been shown to be involved in determination of cell fate and the regulation of embryonic development of many organ systems including heart (Restivo et al., 2006; Schilham et al., 1996), pancreas (Lioubinski et al., 2003; Wilson et al., 2005) and brain (Cheung et al., 2000; Hong and Saint-Jeannet, 2005). SOX4 has been shown to be a transcriptional activator in lymphocytes (van de Wetering et al., 1993) and facilitates B and T cell differentiation (Schilham et al., 1996; Schilham et al., 1997). SOX4 gene expression is up-regulated in many tumor types, with experimental evidence suggesting that this contributes to cellular transformation (Liu et al., 2006; Shin et al., 2004), control of apoptosis (Liu et al., 2006; Pramoonjago et al., 2006; Aaboe et al., 2006; Ahn et al., 2002) and/or a metastatic phenotype (Liao et al., 2008; Tavazoie et al., 2008).
Homology SOX4 is part of a family of Sox transcription factors that share significant homology. SOX4 is in the Group C Sox homology group that includes SOX11, SOX22 and SOX24. SOX4 shares the highest degree of homology with SOX11 (Bowles et al., 2000).

Implicated in

Note
  
Entity Adenoid Cystic Carcinoma (ACC)
Note Gene expression profiling using micro arrays has shown SOX4 is one of the most up-regulated genes in ACC, relative to non-neoplastic tissue of origin (Frierson et al., 2002). Immunohistochemistry analysis confirms the up-regulation of SOX4 in primary ACC tumors compared to normal tissue (Pramoonjago et al., 2006).
Disease ACC is the second most common malignant salivary gland tumor, representing 28% of malignant submandibular gland tumors.
  
  
Entity Bladder Cancer
Note Whole genome expression profiling of 166 bladder tumors and 27 normal samples showed SOX4 up-regulated 5 fold in the tumors. When over-expressed in the bladder cell line HU609, SOX4 strongly impaired cell viability and promoted apoptosis (Aaboe et al., 2006).
Prognosis A correlation was found between strong SOX4 expression levels and increased patient survival.
  
  
Entity Breast Cancer
Note MicroRNA miR335 has been shown to regulate Sox4 levels and is frequently found lost in primary tumors of breast cancer patients who relapse (Tavazoie et al., 2008). In experimental model systems, it appears that SOX4 is a primary gene product associated with metastasis and migration.
  
  
Entity Leukemia
Note SOX4 transcript is found in high levels in B-ALL and T-ALL, but not in AML, CML, CLL, Sezary syndrome, or T cell prolymphocytic leukemia (Mallampati et al., 2008). Retroviral tagging in mouse models suggests a functional role for SOX4 in hematologic malignancies (Shin et al., 2004; Suzuki et al., 2002; Lund et al., 2002).
  
  
Entity Lung Cancer
Note SOX4 is upregulated is a significant percentage of lung cancers (Bangur et al., 2002; Friedman et al., 2004) and antibodies to this protein can be found in the serum of lung cancer patients (Friedman et al., 2004).
  
  
Entity Hepatocellular Carcinoma
Note Experimental manipulation of SOX4 in hepatocellular carcinoma cell line models suggests that SOX4 is pro-apoptotic in this tumor type (Ahn et al., 2002). Paradoxically, another group found that knocking down SOX4 expression in a hepatocellular carcinoma cell line decreased tumorigenicity (Liao et al., 2008).
  
  
Entity Medulloblastoma
Note SOX4 is significantly overexpressed in medulloblastoma compared to normal cerebellum and ependymoma (de Bont et al., 2008; Yokota et al., 2004).
Prognosis A trend was found towards increased survival with increased levels of expression of SOX4.
  
  
Entity Prostate Cancer
Note SOX4 has been show to be over-expressed in prostate tumor samples by microarray analysis, real-time PCR and immunohistochemistry. Additionally, stable transfection of Sox4 into non-transformed prostate cells form colonies in soft agar, suggesting SOX4 can be a transforming oncogene.
  

Bibliography

SOX4 expression in bladder carcinoma: clinical aspects and in vitro functional characterization.
Aaboe M, Birkenkamp-Demtroder K, Wiuf C, Sorensen FB, Thykjaer T, Sauter G, Jensen KM, Dyrskjot L, Orntoft T.
Cancer Res. 2006 Apr 1;66(7):3434-42.
PMID 16585165
 
Sox-4 is a positive regulator of Hep3B and HepG2 cells' apoptosis induced by prostaglandin (PG)A(2) and delta(12)-PGJ(2).
Ahn SG, Kim HS, Jeong SW, Kim BE, Rhim H, Shim JY, Kim JW, Lee JH, Kim IK.
Exp Mol Med. 2002 Jul 31;34(3):243-9.
PMID 12216117
 
Identification of genes over-expressed in small cell lung carcinoma using suppression subtractive hybridization and cDNA microarray expression analysis.
Bangur CS, Switzer A, Fan L, Marton MJ, Meyer MR, Wang T.
Oncogene. 2002 May 23;21(23):3814-25.
PMID 12032850
 
Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators.
Bowles J, Schepers G, Koopman P.
Dev Biol. 2000 Nov 15;227(2):239-55. Review
PMID 11071752
 
Roles of Sox4 in central nervous system development.
Cheung M, Abu-Elmagd M, Clevers H, Scotting PJ.
Brain Res Mol Brain Res. 2000 Jun 23;79(1-2):180-91.
PMID 10925158
 
Molecular and immunological evaluation of the transcription factor SOX-4 as a lung tumor vaccine antigen.
Friedman RS, Bangur CS, Zasloff EJ, Fan L, Wang T, Watanabe Y, Kalos M.
J Immunol. 2004 Mar 1;172(5):3319-27.
PMID 14978140
 
Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma.
Frierson HF Jr, El-Naggar AK, Welsh JB, Sapinoso LM, Su AI, Cheng J, Saku T, Moskaluk CA, Hampton GM.
Am J Pathol. 2002 Oct;161(4):1315-23.
PMID 12368205
 
Sox proteins and neural crest development.
Hong CS, Saint-Jeannet JP.
Semin Cell Dev Biol. 2005 Dec;16(6):694-703. Epub 2005 Jul 21. Review
PMID 16039883
 
Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma.
Liao YL, Sun YM, Chau GY, Chau YP, Lai TC, Wang JL, Horng JT, Hsiao M, Tsou AP.
Oncogene. 2008 May 26. [Epub ahead of print]
PMID 18504433
 
Expression of Sox transcription factors in the developing mouse pancreas.
Lioubinski O, Muller M, Wegner M, Sander M.
Dev Dyn. 2003 Jul;227(3):402-8.
PMID 12815626
 
Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells.
Liu P, Ramachandran S, Ali Seyed M, Scharer CD, Laycock N, Dalton WB, Williams H, Karanam S, Datta MW, Jaye DL, Moreno CS.
Cancer Res. 2006 Apr 15;66(8):4011-9.
PMID 16618720
 
Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice.
Lund AH, Turner G, Trubetskoy A, Verhoeven E, Wientjens E, Hulsman D, Russell R, DePinho RA, Lenz J, van Lohuizen M.
Nat Genet. 2002 Sep;32(1):160-5. Epub 2002 Aug 19.
PMID 12185367
 
Rooting into the soil, a model for the role of Sox4 in leukemia.
Mallampati S, Baohua S, Gong Y, Wang E, You M, Amin H, et al.
American Society of Hematology Annual Meeting; San Francisco, Abstract 3794; CA 2008.
 
Knockdown of Sox4 expression by RNAi induces apoptosis in ACC3 cells.
Pramoonjago P, Baras AS, Moskaluk CA.
Oncogene. 2006 Sep 14;25(41):5626-39. Epub 2006 Apr 24.
PMID 16636670
 
Cardiac outflow tract: a review of some embryogenetic aspects of the conotruncal region of the heart.
Restivo A, Piacentini G, Placidi S, Saffirio C, Marino B.
Anat Rec A Discov Mol Cell Evol Biol. 2006 Sep;288(9):936-43. Review
PMID 16892424
 
Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression.
Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM.
Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9309-14. Epub 2004 Jun 7.
PMID 15184677
 
Sox-4 facilitates thymocyte differentiation.
Schilham MW, Moerer P, Cumano A, Clevers HC.
Eur J Immunol. 1997 May;27(5):1292-5.
PMID 9174623
 
High-throughput retroviral tagging for identification of genes involved in initiation and progression of mouse splenic marginal zone lymphomas.
Shin MS, Fredrickson TN, Hartley JW, Suzuki T, Akagi K, Morse HC 3rd.
Cancer Res. 2004 Jul 1;64(13):4419-27.
PMID 15231650
 
New genes involved in cancer identified by retroviral tagging.
Suzuki T, Shen H, Akagi K, Morse HC, Malley JD, Naiman DQ, Jenkins NA, Copeland NG.
Nat Genet. 2002 Sep;32(1):166-74. Epub 2002 Aug 19.
PMID 12185365
 
Endogenous human microRNAs that suppress breast cancer metastasis.
Tavazoie SF, Alarcon C, Oskarsson T, Padua D, Wang Q, Bos PD, Gerald WL, Massague J.
Nature. 2008 Jan 10;451(7175):147-52.
PMID 18185580
 
The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas.
Wilson ME, Yang KY, Kalousova A, Lau J, Kosaka Y, Lynn FC, Wang J, Mrejen C, Episkopou V, Clevers HC, German MS.
Diabetes. 2005 Dec;54(12):3402-9.
PMID 16306355
 
Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization.
Yokota N, Mainprize TG, Taylor MD, Kohata T, Loreto M, Ueda S, Dura W, Grajkowska W, Kuo JS, Rutka JT.
Oncogene. 2004 Apr 22;23(19):3444-53.
PMID 15064731
 
Differential expression and prognostic significance of SOX genes in pediatric medulloblastoma and ependymoma identified by microarray analysis.
de Bont JM, Kros JM, Passier MM, Reddingius RE, Sillevis Smitt PA, Luider TM, den Boer ML, Pieters R.
Neuro Oncol. 2008 Oct;10(5):648-60. Epub 2008 Jun 24.
PMID 18577562
 
Sox-4, an Sry-like HMG box protein, is a transcriptional activator in lymphocytes.
van de Wetering M, Oosterwegel M, van Norren K, Clevers H.
EMBO J. 1993 Oct;12(10):3847-54.
PMID 8404853
 

Citation

This paper should be referenced as such :
Satinover, DL ; Moskaluk, CA
SOX4 (SRY (sex determining region Y)-box 4)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(12):972-974.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/SOX4ID42358ch6p22.html


External links

Nomenclature
HGNC (Hugo)SOX4   11200
Cards
AtlasSOX4ID42358ch6p22
Entrez_Gene (NCBI)SOX4  6659  SRY-box 4
AliasesEVI16
GeneCards (Weizmann)SOX4
Ensembl hg19 (Hinxton)ENSG00000124766 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000124766 [Gene_View]  chr6:21593741-21598618 [Contig_View]  SOX4 [Vega]
ICGC DataPortalENSG00000124766
TCGA cBioPortalSOX4
AceView (NCBI)SOX4
Genatlas (Paris)SOX4
WikiGenes6659
SOURCE (Princeton)SOX4
Genetics Home Reference (NIH)SOX4
Genomic and cartography
GoldenPath hg38 (UCSC)SOX4  -     chr6:21593741-21598618 +  6p22.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SOX4  -     6p22.3   [Description]    (hg19-Feb_2009)
EnsemblSOX4 - 6p22.3 [CytoView hg19]  SOX4 - 6p22.3 [CytoView hg38]
Mapping of homologs : NCBISOX4 [Mapview hg19]  SOX4 [Mapview hg38]
OMIM184430   
Gene and transcription
Genbank (Entrez)AF070669 AF124147 AJ420500 BC072668 BM459088
RefSeq transcript (Entrez)NM_003107
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)SOX4
Cluster EST : UnigeneHs.643910 [ NCBI ]
CGAP (NCI)Hs.643910
Alternative Splicing GalleryENSG00000124766
Gene ExpressionSOX4 [ NCBI-GEO ]   SOX4 [ EBI - ARRAY_EXPRESS ]   SOX4 [ SEEK ]   SOX4 [ MEM ]
Gene Expression Viewer (FireBrowse)SOX4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6659
GTEX Portal (Tissue expression)SOX4
Human Protein AtlasENSG00000124766-SOX4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ06945   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ06945  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ06945
Splice isoforms : SwissVarQ06945
PhosPhoSitePlusQ06945
Domaine pattern : Prosite (Expaxy)HMG_BOX_2 (PS50118)   
Domains : Interpro (EBI)HMG_box_dom   
Domain families : Pfam (Sanger)HMG_box (PF00505)   
Domain families : Pfam (NCBI)pfam00505   
Domain families : Smart (EMBL)HMG (SM00398)  
Conserved Domain (NCBI)SOX4
DMDM Disease mutations6659
Blocks (Seattle)SOX4
SuperfamilyQ06945
Human Protein Atlas [tissue]ENSG00000124766-SOX4 [tissue]
Peptide AtlasQ06945
HPRD01695
IPIIPI00001617   
Protein Interaction databases
DIP (DOE-UCLA)Q06945
IntAct (EBI)Q06945
FunCoupENSG00000124766
BioGRIDSOX4
STRING (EMBL)SOX4
ZODIACSOX4
Ontologies - Pathways
QuickGOQ06945
Ontology : AmiGOtranscription regulatory region sequence-specific DNA binding  core promoter sequence-specific DNA binding  nucleic acid binding transcription factor activity  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  RNA polymerase II transcription coactivator activity  skeletal system development  neural tube formation  pro-B cell differentiation  mitral valve morphogenesis  cardiac ventricle formation  cardiac right ventricle morphogenesis  atrial septum primum morphogenesis  noradrenergic neuron differentiation  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  mitochondrion  regulation of transcription, DNA-templated  transcription from RNA polymerase II promoter  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  heart development  positive regulation of cell proliferation  negative regulation of cell proliferation  glial cell proliferation  spinal cord development  spinal cord motor neuron differentiation  glial cell development  positive regulation of Wnt signaling pathway  T cell differentiation  endocrine pancreas development  negative regulation of protein ubiquitination  regulation of protein stability  positive regulation of insulin secretion  somatic stem cell population maintenance  ascending aorta morphogenesis  glucose homeostasis  DNA damage response, detection of DNA damage  positive regulation of apoptotic process  nuclear transcription factor complex  positive regulation of translation  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  negative regulation of protein export from nucleus  protein heterodimerization activity  sympathetic nervous system development  protein stabilization  canonical Wnt signaling pathway  limb bud formation  ventricular septum morphogenesis  negative regulation of cell death  neuroepithelial cell differentiation  kidney morphogenesis  cellular response to glucose stimulus  positive regulation of canonical Wnt signaling pathway  positive regulation of N-terminal peptidyl-lysine acetylation  
Ontology : EGO-EBItranscription regulatory region sequence-specific DNA binding  core promoter sequence-specific DNA binding  nucleic acid binding transcription factor activity  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  RNA polymerase II transcription coactivator activity  skeletal system development  neural tube formation  pro-B cell differentiation  mitral valve morphogenesis  cardiac ventricle formation  cardiac right ventricle morphogenesis  atrial septum primum morphogenesis  noradrenergic neuron differentiation  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleoplasm  nucleoplasm  cytoplasm  mitochondrion  regulation of transcription, DNA-templated  transcription from RNA polymerase II promoter  DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest  heart development  positive regulation of cell proliferation  negative regulation of cell proliferation  glial cell proliferation  spinal cord development  spinal cord motor neuron differentiation  glial cell development  positive regulation of Wnt signaling pathway  T cell differentiation  endocrine pancreas development  negative regulation of protein ubiquitination  regulation of protein stability  positive regulation of insulin secretion  somatic stem cell population maintenance  ascending aorta morphogenesis  glucose homeostasis  DNA damage response, detection of DNA damage  positive regulation of apoptotic process  nuclear transcription factor complex  positive regulation of translation  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of transcription from RNA polymerase II promoter  negative regulation of protein export from nucleus  protein heterodimerization activity  sympathetic nervous system development  protein stabilization  canonical Wnt signaling pathway  limb bud formation  ventricular septum morphogenesis  negative regulation of cell death  neuroepithelial cell differentiation  kidney morphogenesis  cellular response to glucose stimulus  positive regulation of canonical Wnt signaling pathway  positive regulation of N-terminal peptidyl-lysine acetylation  
Pathways : KEGGMicroRNAs in cancer   
REACTOMEQ06945 [protein]
REACTOME PathwaysR-HSA-3769402 [pathway]   
NDEx NetworkSOX4
Atlas of Cancer Signalling NetworkSOX4
Wikipedia pathwaysSOX4
Orthology - Evolution
OrthoDB6659
GeneTree (enSembl)ENSG00000124766
Phylogenetic Trees/Animal Genes : TreeFamSOX4
HOVERGENQ06945
HOGENOMQ06945
Homologs : HomoloGeneSOX4
Homology/Alignments : Family Browser (UCSC)SOX4
Gene fusions - Rearrangements
Tumor Fusion PortalSOX4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerSOX4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)SOX4
dbVarSOX4
ClinVarSOX4
1000_GenomesSOX4 
Exome Variant ServerSOX4
ExAC (Exome Aggregation Consortium)ENSG00000124766
GNOMAD BrowserENSG00000124766
Genetic variants : HAPMAP6659
Genomic Variants (DGV)SOX4 [DGVbeta]
DECIPHERSOX4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisSOX4 
Mutations
ICGC Data PortalSOX4 
TCGA Data PortalSOX4 
Broad Tumor PortalSOX4
OASIS PortalSOX4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICSOX4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDSOX4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch SOX4
DgiDB (Drug Gene Interaction Database)SOX4
DoCM (Curated mutations)SOX4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)SOX4 (select a term)
intoGenSOX4
NCG5 (London)SOX4
Cancer3DSOX4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM184430   
Orphanet
DisGeNETSOX4
MedgenSOX4
Genetic Testing Registry SOX4
NextProtQ06945 [Medical]
TSGene6659
GENETestsSOX4
Target ValidationSOX4
Huge Navigator SOX4 [HugePedia]
snp3D : Map Gene to Disease6659
BioCentury BCIQSOX4
ClinGenSOX4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6659
Chemical/Pharm GKB GenePA36037
Clinical trialSOX4
Miscellaneous
canSAR (ICR)SOX4 (select the gene name)
Probes
Litterature
PubMed119 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineSOX4
EVEXSOX4
GoPubMedSOX4
iHOPSOX4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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