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NKX3-1 (NK3 homeobox 1)

Identity

Other namesNKX3
BAPX2
NKX3A
NKX3.1
HGNC (Hugo) NKX3-1
Location 8p21.2
Location_base_pair Starts at 23592152 and ends at 23596395 bp from pter ( according to hg18-Mar_2006)  [Mapping]
Local_order Gene orientation: telomere-3' NKX3.1 5'-centromere.

DNA/RNA

 
  The gene for NKX3-1 comprises two exons of 334 and 2947 bp, respectively. The length of the intron is 964 bp. Positions of start and stop codons are indicated.
Description The gene has two exons and one intron.
Transcription Transcription takes place in a centromere --> telomere orientation. The length of the processed mRNA is about 3200 bp.
Pseudogene Not known.

Protein

 
  NKX3-1 contains two exons encoding a 234-amino acid protein including a homeodomain (grey).
Description 234 amino acids; 35-38 kDa, contains one N-terminal domain (residues 1-123), one homeodomain (residues 124-183), and one C-terminal domain (residues 184-234).
Expression Expression is restricted to the adult murine prostate and bulbourethral gland. During early murine embryogenesis NKX3-1 expression has also been detected in developing somites and testes. In the adult human expression is seen in prostate epithelium, testis, ureter, and pulmonary bronchial mucous glands.
Localisation Nuclear.
Function Binds to DNA to suppress transcription. Interacts with transcription factors, e.g. serum response factor, to enhance transcriptional activation. Binds to and potentiates topoisomerase I DNA resolving activity. Acts as prostate tumor suppressor.
Homology Homeodomain protein with membership of the NKX family.

Mutations

Germinal Twenty-one germ-line variants have been identified in 159 probands of hereditary prostate cancer families. These variants were linked to prostate cancer risk in hereditary prostate cancer families. For example, the C154T (11% of the population) polymorphism mutation is associated with prostatic enlargement and prostate cancer risk. A T164A mutations in one family cosegregates with prostate cancer in three affected brothers. For a more complete list of identified mutations, please visit http://cancerres.aacrjournals.org/cgi/content/full/66/1/69.
Somatic None.

Implicated in

Entity Prostate Cancer
Disease Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of cancer-related deaths. Prostate cancer predominantly occurs in the peripheral zone of the human prostate, with roughly 5 to 10% of cases found in the central zone. Disease development involves the temporal and spatial loss of the basal epithelial compartment accompanied by increased proliferation and dedifferentiation of the luminal (secretory) epithelial cells. Prostate cancer is a slow developing disease that is typically found in men greater than 60 years of age and incidence increases with increasing age.
Prognosis PSA test combined with digital-rectal exams are used to screen for the presence of disease. If the digital-rectal exams are positive, additional tests including needle core biopsies are taken to assess disease stage and grade. Patients with localized, prostate-restricted disease are theoretically curable with complete removal of the prostate (radical prostatectomy). Patients with extra-prostatic disease are treated with hormone (androgen ablation) therapy, radiation, and/or antiandrogens; however, no curative treatments are available for nonorgan confined, metastatic disease.
Cytogenetics Various forms of aneuploidy.
Oncogenesis Nkx3.1 plays an essential role in normal murine prostate development. Loss of function of Nkx3.1 leads to defects in prostatic protein secretions and in ductal morphogenesis. Loss-of-function of Nkx3.1 also contributes to prostate carcinogenesis. For example, Nkx3.1 mutant mice develop prostatic dysplasia. Nkx3.1 loss potentiates prostate carcinogenesis in a Pten+/- background. Furthermore, by a variety of mechanisms NKX3.1 expression is reduced in noninvasive and early stage human prostate cancer, suggesting that its decreased expression is one of the earliest steps in the majority of human prostate cancers.
  

External links

Nomenclature
HGNC (Hugo)NKX3-1   7838
Entrez_Gene (NCBI)NKX3-1  4824  NK3 homeobox 1
Cards
AtlasNKX31ID41541ch8p21
GeneCards (Weizmann)NKX3-1
Ensembl (Hinxton)ENSG00000167034 [Gene_View]  NKX3-1 [Vega]
AceView (NCBI)NKX3-1
Genatlas (Paris)NKX3-1
euGene (Indiana)4824
SOURCE (Stanford)NM_006167
Gene Expression (Array Express) ENSG00000167034
Genomic and cartography
GoldenPath (UCSC)NKX3-1  -  8p21.2   chr8:23592152-23596395 -  8p21   [Description]    (hg18-Mar_2006)
EnsemblNKX3-1 - 8p21 [CytoView]
Mapping of homologs : NCBINKX3-1 [Mapview]
OMIM602041   
Gene and transcription
Gene : Genbank (Entrez)AF247704 AF249669 AF249670 AF249671 AF249672
Reference sequence (RefSeq transcript) :SRSNM_006167
Reference transcript : EntrezNM_006167
RefSeq genomic : SRSAC_000051 AC_000140 NC_000008 NT_167187 NW_001839127 NW_923907
RefSeq genomic : EntrezAC_000051 AC_000140 NC_000008 NT_167187 NW_001839127 NW_923907
Consensus coding sequences : CCDS NCBINKX3-1
Cluster EST : UnigeneHs.55999 [ SRS ] Hs.55999 [ NCBI ]
Alternative Splicing : Fast-db (Paris)2709
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ99801 (SRS) Q99801 (Expasy) Q99801 (Uniprot)
With graphics : InterProQ99801
Splice isoforms : VarSplice FASTAQ99801(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    Homeobox_CS    Homeobox_region    Homeodomain-like    Homeodomain-rel   
Domains : Interpro (EBI)Homeobox    Homeobox_CS    Homeobox_region    Homeodomain-like    Homeodomain-rel   
Related proteins : CluSTrQ99801
Domain families : Pfam SRSHomeobox (PF00046)   
Domain families : Pfam SangerHomeobox (PF00046)   
Domain families : Pfam NCBIpfam00046   
Domain families : Smart EMBLHOX (SM00389)  
Blocks (Seattle)Q99801
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
HPRD03620
Protein Interaction databases
DIP (DOE-UCLA)Q99801
IntAct (EBI)Q99801
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBINKX3-1
SNP : GeneSNP UtahNKX3-1
SNP : HGBaseNKX3-1
Genetic variants : HAPMAPNKX3-1
Somatic Mutations in Cancer : COSMICNKX3-1 
Mutations and Diseases : HGMDNKX3-1
Hereditary diseases : OMIM602041   
Hereditary diseases : GENETests602041   
Diseases : Genetic AssociationNKX3-1
General knowledge
Homologs : HomoloGeneNKX3-1
Homology/Alignments : Family Browser UCSCNKX3-1
Phylogenetic Trees/Animal Genes : TreeFamNKX3-1
Chemical/Protein Interactions : CTD4824
Keywords Ontology : AmiGOsomitogenesis  transcription factor activity  nucleus  regulation of transcription, DNA-dependent  multicellular organismal development  salivary gland development  heart development  transcription factor binding  transcription activator activity  prostate gland development  sequence-specific DNA binding  branching morphogenesis of a tube  negative regulation of epithelial cell proliferation  pharyngeal system development  
Keywords Ontology : EGO-EBIsomitogenesis  transcription factor activity  nucleus  regulation of transcription, DNA-dependent  multicellular organismal development  salivary gland development  heart development  transcription factor binding  transcription activator activity  prostate gland development  sequence-specific DNA binding  branching morphogenesis of a tube  negative regulation of epithelial cell proliferation  pharyngeal system development  
Pathways : BIOCARTA
Pathways : KEGG
Other databases
Probes
Probes : ImagenesNKX3-1 Related clones (RZPD - Berlin)
Literature
PubMed48 Pubmed reference(s) in Entrez
PubGeneNKX3-1

Bibliography

A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer.
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Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers.
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Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression.
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Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens.
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Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate.
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Mech Dev. 2000 Jul;95(1-2):163-74.
PMID 10906459
 
DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1.
Steadman DJ, Giuffrida D, Gelmann EP.
Nucleic Acids Res. 2000 Jun 15;28(12):2389-95.
PMID 10871372
 
Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands.
Tanaka M, Komuro I, Inagaki H, Jenkins NA, Copeland NG, Izumo S.
Dev Dyn. 2000 Oct;219(2):248-60.
PMID 11002344
 
Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer.
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J Urol. 2000 Mar;163(3):972-9.
PMID 10688034
 
Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium.
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J Urol. 2001 Apr;165(4):1329-34.
PMID 11257711
 
Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia.
Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK, Humphrey PA, Milbrandt J.
Mol Cell Biol. 2002 Mar;22(5):1495-503.
PMID 11839815
 
Occurrence of NKX3.1 C154T polymorphism in men with and without prostate cancer and studies of its effect on protein function.
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Cancer Res. 2002 May 1;62(9):2654-9.
PMID 11980664
 
Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis.
Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons R, Shen MM, Abate-Shen C.
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2884-9. Epub 2002 Feb 19.
PMID 11854455
 
Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases.
Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Desai N, Gregg JP, Borowsky AD, Cardiff RD, Shen MM.
Cancer Res. 2003 Jul 15;63(14):3886-90.
PMID 12873978
 
Expression of NKX3.1 in normal and malignant tissues.
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Prostate. 2003 May 1;55(2):111-7.
PMID 12661036
 
Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation.
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Cancer Cell. 2003 Mar;3(3):273-83.
PMID 12676585
 
Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.
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Dev Dyn. 2003 Dec;228(4):767-78.
PMID 14648854
 
Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis.
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J Urol. 2004 Sep;172(3):1134-9.
PMID 15311057
 
Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer.
Asatiani E, Huang WX, Wang A, Rodriguez Ortner E, Cavalli LR, Haddad BR, Gelmann EP.
Cancer Res. 2005 Feb 15;65(4):1164-73.
PMID 15734999
 
Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion.
Bethel CR, Faith D, Li X, Guan B, Hicks JL, Lan F, Jenkins RB, Bieberich CJ, De Marzo AM.
Cancer Res. 2006 Nov 15;66(22):10683-90.
PMID 17108105
 
Physical and functional interactions between the prostate suppressor homeoprotein NKX3.1 and serum response factor.
Ju JH, Maeng JS, Zemedkun M, Ahronovitz N, Mack JW, Ferretti JA, Gelmann EP, Gruschus JM.
J Mol Biol. 2006 Jul 28;360(5):989-99. Epub 2006 Jun 15.
PMID 16814806
 
NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells.
Li X, Guan B, Maghami S, Bieberich CJ.
Mol Cell Biol. 2006 Apr;26(8):3008-17.
PMID 16581776
 
Effect of homeodomain protein NKX3.1 R52C polymorphism on prostate gland size.
Rodriguez Ortner E, Hayes RB, Weissfeld J, Gelmann EP.
Urology. 2006 Feb;67(2):311-5. Epub 2006 Jan 25.
PMID 16442598
 
Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells.
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Biochem J. 2006 Jan 1;393(Pt 1):397-409.
PMID 16201967
 
Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.
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Cancer Res. 2006 Jan 1;66(1):69-77.
PMID 16397218
 
NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity.
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Cancer Res. 2007 Jan 15;67(2):455-64.
PMID 17234752
 
Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation.
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PMID 17602165
 
Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.
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PMID 18557759
 
Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity.
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Cancer Res. 2008 Sep 15;68(18):7380-5.
PMID 18794125
 
Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1.
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PMID 18757402
 
Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor.
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Exp Biol Med (Maywood). 2008 Mar;233(3):297-309.
PMID 18296735
 
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Contributor(s)

Written03-2009Liang-Nian Song, Edward P Gelmann
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA

Citation

This paper should be referenced as such :
Song LN, Gelmann EP . NKX3-1 (NK3 homeobox 1). Atlas Genet Cytogenet Oncol Haematol. March 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/NKX31ID41541ch8p21.html

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