NKX3-1 (NK3 homeobox 1)

2009-03-01 Liang-Nian Song , Edward P Gelmann Affiliation

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA

Identity

HGNC

NKX3-1

LOCATION

8p21.2

LOCUSID

4824

ALIAS

BAPX2,NKX3,NKX3.1,NKX3A

FUSION GENES

Show Gene Fusions

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.

Proteins

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 name

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.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
18557759	2008	Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.	Abate-Shen C et al
11839815	2002	Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia.	Abdulkadir SA et al
15734999	2005	Deletion, methylation, and expression of the NKX3.1 suppressor gene in primary human prostate cancer.	Asatiani E et al
17108105	2006	Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion.	Bethel CR et al
10215624	1999	Roles for Nkx3.1 in prostate development and cancer.	Bhatia-Gaur R et al
11085535	2000	Loss of NKX3.1 expression in human prostate cancers correlates with tumor progression.	Bowen C et al
17234752	2007	NKX3.1 homeodomain protein binds to topoisomerase I and enhances its activity.	Bowen C et al
12661036	2003	Expression of NKX3.1 in normal and malignant tissues.	Gelmann EP et al
9226374	1997	A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer.	He WW et al
18794125	2008	Nkx3-1 and LEF-1 function as transcriptional inhibitors of estrogen receptor activity.	Holmes KA et al
16814806	2006	Physical and functional interactions between the prostate suppressor homeoprotein NKX3.1 and serum response factor.	Ju JH et al
11854455	2002	Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis.	Kim MJ et al
15311057	2004	Analysis of androgen regulated homeobox gene NKX3.1 during prostate carcinogenesis.	Korkmaz CG et al
11137288	2000	Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens.	Korkmaz KS et al
16581776	2006	NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells.	Li X et al
12676585	2003	Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation.	Magee JA et al
18757402	2008	Inflammatory cytokines induce phosphorylation and ubiquitination of prostate suppressor protein NKX3.1.	Markowski MC et al
17602165	2007	Haploinsufficient prostate tumor suppression by Nkx3.1: a role for chromatin accessibility in dosage-sensitive gene regulation.	Mogal AP et al
11257711	2001	Expression studies and mutational analysis of the androgen regulated homeobox gene NKX3.1 in benign and malignant prostate epithelium.	Ornstein DK et al
9537602	1998	Isolation and androgen regulation of the human homeobox cDNA, NKX3.1.	Prescott JL et al
16442598	2006	Effect of homeodomain protein NKX3.1 R52C polymorphism on prostate gland size.	Rodriguez Ortner E et al
10906459	2000	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 et al
9142502	1997	Tissue-specific expression of murine Nkx3.1 in the male urogenital system.	Sciavolino PJ et al
14648854	2003	Roles of the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.	Shen MM et al
16201967	2006	Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells.	Simmons SO et al
10871372	2000	DNA-binding sequence of the human prostate-specific homeodomain protein NKX3.1.	Steadman DJ et al
11002344	2000	Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands.	Tanaka M et al
10415359	1999	Expression of the Nkx3.1 homobox gene during pre and postnatal development.	Tanaka M et al
9377551	1997	Coding region of NKX3.1, a prostate-specific homeobox gene on 8p21, is not mutated in human prostate cancers.	Voeller HJ et al
10688034	2000	Expression profile of an androgen regulated prostate specific homeobox gene NKX3.1 in primary prostate cancer.	Xu LL et al
18296735	2008	Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor.	Zhang Y et al
16397218	2006	Germ-line mutation of NKX3.1 cosegregates with hereditary prostate cancer and alters the homeodomain structure and function.	Zheng SL et al

Other Information

Locus ID:

NCBI: 4824
MIM: 602041
HGNC: 7838
Ensembl: ENSG00000167034

Variants:

dbSNP: 4824
ClinVar: 4824
TCGA: ENSG00000167034
COSMIC: NKX3-1

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000167034	ENST00000380871	Q99801
ENSG00000167034	ENST00000523261	Q99801

Expression (GTEx)

100

150

200

250

300

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
Prostate cancer	KEGG	ko05215
Pathways in cancer	KEGG	hsa05200
Prostate cancer	KEGG	hsa05215

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
38525603	2024	NKX3.1 Expression in Non-Prostatic Tumors and Characterizing its Expression in Esophageal/Gastroesophageal Adenocarcinoma.	0
38525603	2024	NKX3.1 Expression in Non-Prostatic Tumors and Characterizing its Expression in Esophageal/Gastroesophageal Adenocarcinoma.	0
36746884	2023	NKX3.1 Expression and Molecular Characterization of Secretory Myoepithelial Carcinoma (SMCA): Advancing the Case for a Salivary Mucous Acinar Phenotype.	1
37334663	2023	Fibroblast-derived exosomal microRNA regulates NKX3-1 expression in androgen-sensitive, androgen receptor-dependent prostate cancer cells.	1
37893500	2023	Comprehensive Analysis of NKX3.2 in Liver Hepatocellular Carcinoma by Bigdata.	0
36746884	2023	NKX3.1 Expression and Molecular Characterization of Secretory Myoepithelial Carcinoma (SMCA): Advancing the Case for a Salivary Mucous Acinar Phenotype.	1
37334663	2023	Fibroblast-derived exosomal microRNA regulates NKX3-1 expression in androgen-sensitive, androgen receptor-dependent prostate cancer cells.	1
37893500	2023	Comprehensive Analysis of NKX3.2 in Liver Hepatocellular Carcinoma by Bigdata.	0
34996754	2022	Gene of the month: NKX3.1.	3
35968571	2022	Genome-Wide 3'-UTR Single Nucleotide Polymorphism Association Study Identifies Significant Prostate Cancer Risk-Associated Functional Loci at 8p21.2 in Chinese Population.	5
34996754	2022	Gene of the month: NKX3.1.	3
35968571	2022	Genome-Wide 3'-UTR Single Nucleotide Polymorphism Association Study Identifies Significant Prostate Cancer Risk-Associated Functional Loci at 8p21.2 in Chinese Population.	5
33302222	2021	NKX3.1 a useful marker for mesenchymal chondrosarcoma: An immunohistochemical study.	11
33640159	2021	NKX3.1 immunohistochemistry is highly specific for the diagnosis of mesenchymal chondrosarcomas: experience in the Australian population.	2
34686726	2021	Nkx3-1 and Fech genes might be switch genes involved in pituitary non-functioning adenoma invasiveness.	4

Citation

Liang-Nian Song ; Edward P Gelmann

NKX3-1 (NK3 homeobox 1)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/41541/css/lib/tumors-explorer/welcome