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MSX2 (Msh Homeobox 2)

Identity

Other namesCRS2
FPP
HOX8
MSH
PFM
PFM1
HGNC (Hugo) MSX2
LocusID (NCBI) 4488
Location 5q35.2
Location_base_pair Starts at 174151575 and ends at 174157902 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description MSX2 contains two exons. The length of MSX2 gene is 6328 bases.
Transcription 2224 bases mRNA; 801 bases of coding region.
Pseudogene One pseudogene was reported (Hodgkinson et al., 1993).

Protein

Description This gene encodes a member of the muscle segment homeobox gene family that consists of 267 amino acids. The molecular weight of the encoded protein is about 29 kDa. MSX2 is a transcriptional repressor which regulates a balance between survival and apoptosis of neural crest-derived cells for proper craniofacial morphogenesis (Davidson, 1995). MSX2 is also shown to be an important target for the RAS signaling pathways (Takahashi et al., 1996). The expression pattern of this gene in the development of organs suggests its pivotal role in epithelial-mesenchymal interactions (Satoh et al., 2004). On the other hand, accumulating evidence has revealed the active involvement of this gene in tumorigenesis and/or tumor development (Satoh et al., 2012).
Expression The expression of MSX2 is observed in a variety of sites, including premigratory cranial neural crest, tooth, and mammary gland, etc (Takahashi and Le Douarin, 1990; Davidson, 1995; Satoh et al., 2004). In addition, enhanced expression of MSX2 is found in several cancer species (Satoh et al., 2012).
Localisation Located at cell nuclei.
Function MSX2 act as a transcriptional regulator in the development multiple organs such as bone, neural crest and mammary gland, and play a role in limb-pattern and teeth formation (Davidson, 1995). MSX2 may induce the proliferation of osteoprogenitors (Dodig et al., 1999), as well as osteoblasts (Liu et al., 1999), and this gene was also related to the enhancement of branching morphogenesis in mouse mammary ducts (Satoh et al., 2007).
Homology Mus musculus Msx2; Xenopus laevis msx2-A; Drosophila melanogaster Dr.

Mutations

Germinal Mutations in this gene are associated with Boston type craniosynostosis (Jabs et al., 1993).

Implicated in

Entity Pancreatic cancer
Note MSX2 is shown to be indispensable for BMP-induced epithelial to mesenchymal transition (EMT) in pancreatic cancer cells (Hamada et al., 2007) . Increased expression of this gene was significantly correlated with higher tumor grade, vascular invasion and Twist 1 expression (Satoh, et al., 2008). In addition, MSX2 has been shown to enhance the chemoresistance through ABCG2 induction and increase in the cancer stem cell phenotype (Hamada et al., 2012; Satoh et al., 2012) (Figure 1).
 
  
Entity Gastric cancer
Note MSX2 was identified as a cancer- specific hedgehog target and the down-regulation of this gene resulted in the inhibition of cancer cell growth in vitro (Ohta et al., 2009).
  
Entity Ovarian cancer
Note MSX2 has been shown to be a downstream target of WNT signal and has been correlated with the invasiveness of ovarian endometrioid adenocarcinoma (Zhai et al., 2011).
  
Entity Breast carcinoma
Note The expression of this gene was associated with good prognosis in breast cancer patients (Lanigan et al., 2010).
  
Entity Malignant melanoma
Note The expression of this gene was associated with good prognosis in malignant melanoma patients (Gremel et al., 2011).
  
Entity Prostate carcinoma
Note This gene expression was increased significantly in tumors with metastasis compared to those without metastasis in prostate carcinoma (Chua et al., 2010).
  

External links

Nomenclature
HGNC (Hugo)MSX2   7392
Cards
AtlasMSX2ID41438ch5q35.tx
Entrez_Gene (NCBI)MSX2  4488  msh homeobox 2
GeneCards (Weizmann)MSX2
Ensembl (Hinxton)ENSG00000120149 [Gene_View]  chr5:174151575-174157902 [Contig_View]  MSX2 [Vega]
ICGC DataPortalENSG00000120149
cBioPortalMSX2
AceView (NCBI)MSX2
Genatlas (Paris)MSX2
WikiGenes4488
SOURCE (Princeton)NM_002449
Genomic and cartography
GoldenPath (UCSC)MSX2  -  5q35.2   chr5:174151575-174157902 +  5q35.2   [Description]    (hg19-Feb_2009)
EnsemblMSX2 - 5q35.2 [CytoView]
Mapping of homologs : NCBIMSX2 [Mapview]
OMIM123101   168500   168550   604757   
Gene and transcription
Genbank (Entrez)AL552909 BC015509 BT009814 D14970 D26145
RefSeq transcript (Entrez)NM_002449
RefSeq genomic (Entrez)AC_000137 NC_000005 NC_018916 NG_008124 NT_023133 NW_001838954 NW_004929325
Consensus coding sequences : CCDS (NCBI)MSX2
Cluster EST : UnigeneHs.89404 [ NCBI ]
CGAP (NCI)Hs.89404
Alternative Splicing : Fast-db (Paris)GSHG0024483
Alternative Splicing GalleryENSG00000120149
Gene ExpressionMSX2 [ NCBI-GEO ]     MSX2 [ SEEK ]   MSX2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP35548 (Uniprot)
NextProtP35548  [Medical]
With graphics : InterProP35548
Splice isoforms : SwissVarP35548 (Swissvar)
Domaine pattern : Prosite (Expaxy)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (EBI)Homeobox_CS [organisation]   Homeobox_dom [organisation]   Homeobox_metazoa [organisation]   Homeodomain-like [organisation]  
Related proteins : CluSTrP35548
Domain families : Pfam (Sanger)Homeobox (PF00046)   
Domain families : Pfam (NCBI)pfam00046   
Domain families : Smart (EMBL)HOX (SM00389)  
DMDM Disease mutations4488
Blocks (Seattle)P35548
Human Protein AtlasENSG00000120149 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP35548
HPRD00421
IPIIPI00292686   IPI00964873   
Protein Interaction databases
DIP (DOE-UCLA)P35548
IntAct (EBI)P35548
FunCoupENSG00000120149
BioGRIDMSX2
InParanoidP35548
Interologous Interaction database P35548
IntegromeDBMSX2
STRING (EMBL)MSX2
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity  osteoblast differentiation  chondrocyte development  osteoblast development  outflow tract septum morphogenesis  epithelial to mesenchymal transition involved in endocardial cushion formation  endochondral bone growth  transcription cofactor activity  protein binding  nucleus  transcription factor complex  cytoplasm  transcription factor binding  negative regulation of cell proliferation  anterior/posterior pattern specification  signal transduction involved in regulation of gene expression  positive regulation of BMP signaling pathway  negative regulation of CREB transcription factor activity  embryonic forelimb morphogenesis  embryonic hindlimb morphogenesis  wound healing, spreading of epidermal cells  embryonic nail plate morphogenesis  anagen  positive regulation of apoptotic process  negative regulation of apoptotic process  sequence-specific DNA binding  transcription regulatory region DNA binding  negative regulation of fat cell differentiation  negative regulation of keratinocyte differentiation  positive regulation of osteoblast differentiation  negative regulation of transcription, DNA-dependent  positive regulation of catagen  bone trabecula formation  cranial suture morphogenesis  frontal suture morphogenesis  branching involved in mammary gland duct morphogenesis  BMP signaling pathway involved in heart development  enamel mineralization  cellular response to growth factor stimulus  cellular response to estradiol stimulus  negative regulation of transcription regulatory region DNA binding  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity  osteoblast differentiation  chondrocyte development  osteoblast development  outflow tract septum morphogenesis  epithelial to mesenchymal transition involved in endocardial cushion formation  endochondral bone growth  transcription cofactor activity  protein binding  nucleus  transcription factor complex  cytoplasm  transcription factor binding  negative regulation of cell proliferation  anterior/posterior pattern specification  signal transduction involved in regulation of gene expression  positive regulation of BMP signaling pathway  negative regulation of CREB transcription factor activity  embryonic forelimb morphogenesis  embryonic hindlimb morphogenesis  wound healing, spreading of epidermal cells  embryonic nail plate morphogenesis  anagen  positive regulation of apoptotic process  negative regulation of apoptotic process  sequence-specific DNA binding  transcription regulatory region DNA binding  negative regulation of fat cell differentiation  negative regulation of keratinocyte differentiation  positive regulation of osteoblast differentiation  negative regulation of transcription, DNA-dependent  positive regulation of catagen  bone trabecula formation  cranial suture morphogenesis  frontal suture morphogenesis  branching involved in mammary gland duct morphogenesis  BMP signaling pathway involved in heart development  enamel mineralization  cellular response to growth factor stimulus  cellular response to estradiol stimulus  negative regulation of transcription regulatory region DNA binding  
Pathways : KEGGHTLV-I infection   
Protein Interaction DatabaseMSX2
Wikipedia pathwaysMSX2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MSX2
snp3D : Map Gene to Disease4488
SNP (GeneSNP Utah)MSX2
SNP : HGBaseMSX2
Genetic variants : HAPMAPMSX2
Exome VariantMSX2
1000_GenomesMSX2 
ICGC programENSG00000120149 
Somatic Mutations in Cancer : COSMICMSX2 
CONAN: Copy Number AnalysisMSX2 
Mutations and Diseases : HGMDMSX2
Genomic VariantsMSX2  MSX2 [DGVbeta]
dbVarMSX2
ClinVarMSX2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM123101    168500    168550    604757   
MedgenMSX2
GENETestsMSX2
Disease Genetic AssociationMSX2
Huge Navigator MSX2 [HugePedia]  MSX2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMSX2
Homology/Alignments : Family Browser (UCSC)MSX2
Phylogenetic Trees/Animal Genes : TreeFamMSX2
Chemical/Protein Interactions : CTD4488
Chemical/Pharm GKB GenePA31197
Clinical trialMSX2
Cancer Resource (Charite)ENSG00000120149
Other databases
Probes
Litterature
PubMed78 Pubmed reference(s) in Entrez
CoreMineMSX2
iHOPMSX2

Bibliography

cDNA cloning of a quail homeobox gene and its expression in neural crest-derived mesenchyme and lateral plate mesoderm.
Takahashi Y, Le Douarin N.
Proc Natl Acad Sci U S A. 1990 Oct;87(19):7482-6.
PMID 1977161
 
Expression of a human homeobox-containing gene is regulated by 1,25(OH)2D3 in bone cells.
Hodgkinson JE, Davidson CL, Beresford J, Sharpe PT.
Biochim Biophys Acta. 1993 Jul 18;1174(1):11-6.
PMID 8101453
 
A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis.
Jabs EW, Muller U, Li X, Ma L, Luo W, Haworth IS, Klisak I, Sparkes R, Warman ML, Mulliken JB, et al.
Cell. 1993 Nov 5;75(3):443-50.
PMID 8106171
 
The function and evolution of Msx genes: pointers and paradoxes.
Davidson D.
Trends Genet. 1995 Oct;11(10):405-11. (REVIEW)
PMID 7482767
 
Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene.
Takahashi C, Akiyama N, Matsuzaki T, Takai S, Kitayama H, Noda M.
Oncogene. 1996 May 16;12(10):2137-46.
PMID 8668339
 
Ectopic Msx2 overexpression inhibits and Msx2 antisense stimulates calvarial osteoblast differentiation.
Dodig M, Tadic T, Kronenberg MS, Dacic S, Liu YH, Maxson R, Rowe DW, Lichtler AC.
Dev Biol. 1999 May 15;209(2):298-307.
PMID 10328922
 
Msx2 gene dosage influences the number of proliferative osteogenic cells in growth centers of the developing murine skull: a possible mechanism for MSX2-mediated craniosynostosis in humans.
Liu YH, Tang Z, Kundu RK, Wu L, Luo W, Zhu D, Sangiorgi F, Snead ML, Maxson RE.
Dev Biol. 1999 Jan 15;205(2):260-74.
PMID 9917362
 
Msx-1 and Msx-2 in mammary gland development.
Satoh K, Ginsburg E, Vonderhaar BK.
J Mammary Gland Biol Neoplasia. 2004 Apr;9(2):195-205. (REVIEW)
PMID 15300013
 
Bone morphogenetic protein 4 induces epithelial-mesenchymal transition through MSX2 induction on pancreatic cancer cell line.
Hamada S, Satoh K, Hirota M, Kimura K, Kanno A, Masamune A, Shimosegawa T.
J Cell Physiol. 2007 Dec;213(3):768-74.
PMID 17516553
 
Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2.
Satoh K, Hovey RC, Malewski T, Warri A, Goldhar AS, Ginsburg E, Saito K, Lydon JP, Vonderhaar BK.
Oncogene. 2007 Nov 29;26(54):7526-34. Epub 2007 Jun 4.
PMID 17546050
 
Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells.
Satoh K, Hamada S, Kimura K, Kanno A, Hirota M, Umino J, Fujibuchi W, Masamune A, Tanaka N, Miura K, Egawa S, Motoi F, Unno M, Vonderhaar BK, Shimosegawa T.
Am J Pathol. 2008 Apr;172(4):926-39. doi: 10.2353/ajpath.2008.070346. Epub 2008 Mar 18.
PMID 18349132
 
Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers.
Ohta H, Aoyagi K, Fukaya M, Danjoh I, Ohta A, Isohata N, Saeki N, Taniguchi H, Sakamoto H, Shimoda T, Tani T, Yoshida T, Sasaki H.
Br J Cancer. 2009 Jan 27;100(2):389-98. doi: 10.1038/sj.bjc.6604846. Epub 2008 Dec 23.
PMID 19107131
 
Differential expression of MSX2 in nodular hyperplasia, high-grade prostatic intraepithelial neoplasia and prostate adenocarcinoma.
Chua CW, Chiu YT, Yuen HF, Chan KW, Wang X, Ling MT, Wong YC.
APMIS. 2010 Dec;118(12):918-26. doi: 10.1111/j.1600-0463.2010.02626.x. Epub 2010 Oct 13.
PMID 21091772
 
Homeobox transcription factor muscle segment homeobox 2 (Msx2) correlates with good prognosis in breast cancer patients and induces apoptosis in vitro.
Lanigan F, Gremel G, Hughes R, Brennan DJ, Martin F, Jirstrom K, Gallagher WM.
Breast Cancer Res. 2010;12(4):R59. doi: 10.1186/bcr2621. Epub 2010 Aug 3.
PMID 20682066
 
Functional and prognostic relevance of the homeobox protein MSX2 in malignant melanoma.
Gremel G, Ryan D, Rafferty M, Lanigan F, Hegarty S, Lavelle M, Murphy I, Unwin L, Joyce C, Faller W, McDermott EW, Sheahan K, Ponten F, Gallagher WM.
Br J Cancer. 2011 Aug 9;105(4):565-74. doi: 10.1038/bjc.2011.249. Epub 2011 Jul 5.
PMID 21730974
 
MSX2 is an oncogenic downstream target of activated WNT signaling in ovarian endometrioid adenocarcinoma.
Zhai Y, Iura A, Yeasmin S, Wiese AB, Wu R, Feng Y, Fearon ER, Cho KR.
Oncogene. 2011 Oct 6;30(40):4152-62. doi: 10.1038/onc.2011.123. Epub 2011 Apr 18.
PMID 21499300
 
The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2.
Hamada S, Satoh K, Hirota M, Kanno A, Umino J, Ito H, Masamune A, Kikuta K, Kume K, Shimosegawa T.
J Cell Physiol. 2012 Feb;227(2):729-38. doi: 10.1002/jcp.22781.
PMID 21465479
 
MSX2 in pancreatic tumor development and its clinical application for the diagnosis of pancreatic ductal adenocarcinoma.
Satoh K, Hamada S, Shimosegawa T.
Front Physiol. 2012 Nov 14;3:430. doi: 10.3389/fphys.2012.00430. eCollection 2012.
PMID 23162473
 
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Contributor(s)

Written11-2013Kennichi Satoh
Division of Cancer stem cell, Miyagi Cancer Center Research Institute, 47-1 Nodayama, Shiote, Medeshima, Natori city, Miyagi 981-1293, Japan

Citation

This paper should be referenced as such :
Satoh K
MSX2 (Msh Homeobox 2);
Atlas Genet Cytogenet Oncol Haematol. November 2013
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/MSX2ID41438ch5q35.html

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indexed on : Fri Jul 11 17:19:43 CEST 2014

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