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NKX3-1 (NK3 homeobox 1)

Written2009-03Liang-Nian Song, Edward P Gelmann
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA

(Note : for Links provided by Atlas : click)

Identity

Other aliasNKX3
BAPX2
NKX3A
NKX3.1
LocusID (NCBI) 4824
Atlas_Id 41541
Location 8p21.2  [Link to chromosome band 8p21]
Location_base_pair Starts at and ends at bp from pter
Local_order Gene orientation: telomere-3' NKX3.1 5'-centromere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
NKX3-1 (8p21.2) / SNRPD1 (18q11.2)

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

Note
  
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.
  

Bibliography

Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.
Abate-Shen C, Shen MM, Gelmann E.
Differentiation. 2008 Jul;76(6):717-27. Epub 2008 Jun 28.
PMID 18557759
 
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
 
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
 
Roles for Nkx3.1 in prostate development and cancer.
Bhatia-Gaur R, Donjacour AA, Sciavolino PJ, Kim M, Desai N, Young P, Norton CR, Gridley T, Cardiff RD, Cunha GR, Abate-Shen C, Shen MM.
Genes Dev. 1999 Apr 15;13(8):966-77.
PMID 10215624
 
Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression.
Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP, Gelmann EP.
Cancer Res. 2000 Nov 1;60(21):6111-5.
PMID 11085535
 
NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity.
Bowen C, Stuart A, Ju JH, Tuan J, Blonder J, Conrads TP, Veenstra TD, Gelmann EP.
Cancer Res. 2007 Jan 15;67(2):455-64.
PMID 17234752
 
Expression of NKX3.1 in normal and malignant tissues.
Gelmann EP, Bowen C, Bubendorf L.
Prostate. 2003 May 1;55(2):111-7.
PMID 12661036
 
A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer.
He WW, Sciavolino PJ, Wing J, Augustus M, Hudson P, Meissner PS, Curtis RT, Shell BK, Bostwick DG, Tindall DJ, Gelmann EP, Abate-Shen C, Carter KC.
Genomics. 1997 Jul 1;43(1):69-77.
PMID 9226374
 
Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity.
Holmes KA, Song JS, Liu XS, Brown M, Carroll JS.
Cancer Res. 2008 Sep 15;68(18):7380-5.
PMID 18794125
 
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
 
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
 
Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis.
Korkmaz CG, Korkmaz KS, Manola J, Xi Z, Risberg B, Danielsen H, Kung J, Sellers WR, Loda M, Saatcioglu F.
J Urol. 2004 Sep;172(3):1134-9.
PMID 15311057
 
Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens.
Korkmaz KS, Korkmaz CG, Ragnhildstveit E, Kizildag S, Pretlow TG, Saatcioglu F.
Gene. 2000 Dec 30;260(1-2):25-36.
PMID 11137288
 
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
 
Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation.
Magee JA, Abdulkadir SA, Milbrandt J.
Cancer Cell. 2003 Mar;3(3):273-83.
PMID 12676585
 
Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1.
Markowski MC, Bowen C, Gelmann EP.
Cancer Res. 2008 Sep 1;68(17):6896-901.
PMID 18757402
 
Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation.
Mogal AP, van der Meer R, Crooke PS, Abdulkadir SA.
J Biol Chem. 2007 Aug 31;282(35):25790-800. Epub 2007 Jun 30.
PMID 17602165
 
Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium.
Ornstein DK, Cinquanta M, Weiler S, Duray PH, Emmert-Buck MR, Vocke CD, Linehan WM, Ferretti JA.
J Urol. 2001 Apr;165(4):1329-34.
PMID 11257711
 
Isolation and androgen regulation of the human homeobox cDNA, NKX3.1.
Prescott JL, Blok L, Tindall DJ.
Prostate. 1998 Apr 1;35(1):71-80.
PMID 9537602
 
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
 
Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate.
Schneider A, Brand T, Zweigerdt R, Arnold H.
Mech Dev. 2000 Jul;95(1-2):163-74.
PMID 10906459
 
Tissue-specific expression of murine Nkx3.1 in the male urogenital system.
Sciavolino PJ, Abrams EW, Yang L, Austenberg LP, Shen MM, Abate-Shen C.
Dev Dyn. 1997 May;209(1):127-38.
PMID 9142502
 
Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.
Shen MM, Abate-Shen C.
Dev Dyn. 2003 Dec;228(4):767-78.
PMID 14648854
 
Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells.
Simmons SO, Horowitz JM.
Biochem J. 2006 Jan 1;393(Pt 1):397-409.
PMID 16201967
 
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 of the Nkx3.1 homobox gene during pre and postnatal development.
Tanaka M, Lyons GE, Izumo S.
Mech Dev. 1999 Jul;85(1-2):179-82.
PMID 10415359
 
Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers.
Voeller HJ, Augustus M, Madike V, Bova GS, Carter KC, Gelmann EP.
Cancer Res. 1997 Oct 15;57(20):4455-9.
PMID 9377551
 
Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer.
Xu LL, Srikantan V, Sesterhenn IA, Augustus M, Dean R, Moul JW, Carter KC, Srivastava S.
J Urol. 2000 Mar;163(3):972-9.
PMID 10688034
 
Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor.
Zhang Y, Fillmore RA, Zimmer WE.
Exp Biol Med (Maywood). 2008 Mar;233(3):297-309.
PMID 18296735
 
Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.
Zheng SL, Ju JH, Chang BL, Ortner E, Sun J, Isaacs SD, Sun J, Wiley KE, Liu W, Zemedkun M, Walsh PC, Ferretti J, Gruschus J, Isaacs WB, Gelmann EP, Xu J.
Cancer Res. 2006 Jan 1;66(1):69-77.
PMID 16397218
 

Citation

This paper should be referenced as such :
Song, LN ; Gelmann, EP
NKX3-1 (NK3 homeobox 1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(3):246-248.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/NKX31ID41541ch8p21.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  Prostate tumors: an overview


External links

Nomenclature
Cards
AtlasNKX31ID41541ch8p21.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)4824
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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indexed on : Thu Oct 18 17:45:24 CEST 2018

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