NKX3-1

Last updated

NKX3-1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NKX3-1 , BAPX2, NKX3, NKX3.1, NKX3A, NK3 homeobox 1
External IDs OMIM: 602041; MGI: 97352; HomoloGene: 4494; GeneCards: NKX3-1; OMA:NKX3-1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001256339
NM_006167

NM_010921

RefSeq (protein)

NP_001243268
NP_006158

NP_035051

Location (UCSC) Chr 8: 23.68 – 23.68 Mb Chr 14: 69.43 – 69.43 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Homeobox protein Nkx-3.1, also known as NKX3-1, NKX3, BAPX2, NKX3A and NKX3.1 is a protein that in humans is encoded by the NKX3-1 gene located on chromosome 8p. [5] NKX3-1 is a prostatic tumor suppressor gene.

Contents

NKX3-1 is an androgen-regulated, prostate-specific homeobox gene whose expression is predominantly localized to prostate epithelium. It acts as a transcription factor that has critical function in prostate development and tumor suppression. It is a negative regulator of epithelial cell growth in prostate tissue. The NKX3-1 homeobox protein is encoded by the NKX3-1 gene. [5]

Function

The homeodomain-containing transcription factor NKX3A is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3A protein expression is a common finding in human prostate carcinomas and prostatic intraepithelial neoplasia. [6]

Gene

In humans, the NKX3-1 gene is located on chromosome 8p21.2 with 4 exons. [7] The 8p chromosome is a region that is frequently reported to undergo a loss of heterozygosity (LOH) associated with tissue dedifferentiation and loss of androgen responsiveness during the progression of prostate cancer. LOH has been reported to be observed in 12-89% of high-grade prostatic intraepithelial neoplasia (PIN) and 35-86% of prostatic adenocarcinomas. The frequency of loss of heterozygosity on chromosome 8p is seen to increase with advanced prostate cancer grade and stage. [8]

Structure

NKX3-1 contains two exons encoding a 234 amino acid protein including a homeodomain. The 234 amino acids are 35-38 kDa. One N-terminal domain one homeodomain and one C-terminal domain are present. The observed interaction between NKX3-1 and Serum Response Factor (SRF)indicate that amino-terminal domains participate in the interaction. The synergistic transcriptional activation requires both interactions at multiple protein-protein interfaces and protein-DNA interactions. This indicates that one mechanism of NKX3-1 dependent transcriptional activation in prostate epithelia requires combinatorial interactions with other factors expressed within those cells [9]

In 2000, full length NKX3-1 cDNA was obtained from a human prostate cDNA library. Korkmaz et al. [10] identified 3 splice variants with deletions in the N-terminal region as well as a variant at position 137 within the homeobox domain. NKX3-1 expression was visualized using Fluorescence microscopy, utilizing GFP-NKX3-1 in the nucleus.

Function

NKX3-1 expression acts as a transcription factor that has been found to play a main role in prostate development and tumor suppression. The loss of NKX3-1 expression is frequently observed in prostate tumorigenesis and has been seen to be a result of allelic loss, methylation, and post transcriptional silencing. [11] NKX3-1 expression is seen in prostate epithelium, testis, ureter, and pulmonary bronchial mucous glands.

NKX3-1 binds to DNA to suppress transcription as well as interacts with transcription factors such as serum response factor, to enhance transcriptional activation. Wang et al. [12] demonstrated that NKX3-1 marks a stem cell population that functions during prostate regeneration. Genetic lineage marking demonstrated that rare luminal cells that express NKX3-1 in the absence of testicular androgens are bipotential and can self-renew in vivo. Single-cell transplantation assays showed that castration-resistant NKX3-1 expressing cells (CARNs) can reconstitute prostate ducts in renal grafts. Functional assays of NKX3-1 mutant mice in serial prostate regeneration suggested that NKX3-1 is required for stem cell maintenance. Furthermore, targeted deletion of PTEN gene in CARNs resulted in rapid carcinoma formation after androgen-mediated regeneration. This indicates that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.

It has also been found to be essential in pluripotency of stem cells using Yamanaka factors. [13]

Regulation

In 2010 it was shown that NKX3-1 was controlled by ERG and ESE3 both directly and through induction of EZH2 (Polycomb group pcg). [14]

Discovery

Using a random cDNA sequencing approach, He et al. [15] cloned a novel prostate-specific gene that encoded a homeobox-containing protein. The gene which they symbolized NKX3-1 encoded a 234-amino acid polypeptide with greatest homology to the Drosophila NK3 gene. Northern blot analysis showed that NKX3.1 had a uniquely restricted tissue expression pattern with mRNA being abundant in the prostate, lower levels in the testis and absent from all other tissues tested. The NKX3-1 protein expression was detected a hormone-responsive, androgen receptor-positive prostate cancer cell line, but was absent from androgen receptor-negative prostate cancer cell lines as well as other cell lines of varied origins. The link between androgen stimulation and NKX3-1 was discovered through the use of an androgen-dependent carcinoma line. The researchers suggested that the NKX3-1 gene plays a role in androgen-driven differentiation of prostatic tissue as well as in loss of differentiation during the progression of prostate cancer.

Role in disease

Prostate cancer is the most commonly diagnosed cancer in American men and the second leading cause of cancer related deaths. [16] Prostate cancer predominantly occurs in the peripheral zone of the human prostate, with fewer than 10% of cases found in the central zone. The disease develops as a result of the temporal and spatial loss of the basal epithelial compartment as well as increased proliferation and dedifferentiation of the luminal (secretory) epithelial cells. Prostate cancer is typically found in men of ages older than 60 and its incidence increases with increasing age.

NKX3-1 plays an essential role in normal murine prostate development. Loss of function of NKX3-1 leads to defects in prostatic protein secretions as well as ductal morphogenesis. Loss of function also contributes to prostate carcinogenesis.

Furthermore, immunohistochemistry using anti-NKX3-1 antibodies provides a sensitive and specific method for diagnosing metastatic prostatic adenocarcinomas in distant sites. [17]

Interactions

NKX3-1 has been shown to interact with SPDEF. [18]

The stability of NKX3-1 protein has been shown to be regulated by phosphorylation. [19]

Related Research Articles

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">Homeobox</span> DNA pattern affecting anatomy development

A homeobox is a DNA sequence, around 180 base pairs long, that regulates large-scale anatomical features in the early stages of embryonic development. Mutations in a homeobox may change large-scale anatomical features of the full-grown organism.

<span class="mw-page-title-main">Mothers against decapentaplegic homolog 3</span> Protein-coding gene in humans

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.

<span class="mw-page-title-main">KLF6</span> Protein-coding gene in the species Homo sapiens

Krueppel-like factor 6 is a protein that in humans is encoded by the KLF6 gene.

<span class="mw-page-title-main">FHL2</span> Protein-coding gene in the species Homo sapiens

Four and a half LIM domains protein 2 also known as FHL-2 is a protein that in humans is encoded by the FHL2 gene. LIM proteins contain a highly conserved double zinc finger motif called the LIM domain.

<span class="mw-page-title-main">NDRG1</span> Protein-coding gene in the species Homo sapiens

Protein NDRG1 is a protein that in humans is encoded by the NDRG1 gene.

<span class="mw-page-title-main">HOXA5</span> Protein-coding gene in humans

Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.

<span class="mw-page-title-main">KLK4</span> Mammalian protein found in Homo sapiens

Kallikrein-related peptidase 4 is a protein which in humans is encoded by the KLK4 gene.

<span class="mw-page-title-main">DLC1</span> Protein-coding gene in the species Homo sapiens

Deleted in Liver Cancer 1 also known as DLC1 and StAR-related lipid transfer protein 12 (STARD12) is a protein which in humans is encoded by the DLC1 gene.

<span class="mw-page-title-main">HOXC8</span> Protein-coding gene in the species Homo sapiens

Homeobox protein Hox-C8 is a protein that in humans is encoded by the HOXC8 gene.

<span class="mw-page-title-main">HOXB13</span> Protein-coding gene in the species Homo sapiens

Homeobox protein Hox-B13 is a protein that in humans is encoded by the HOXB13 gene.

<span class="mw-page-title-main">UXT</span> Protein-coding gene in the species Homo sapiens

Protein UXT also known as androgen receptor trapped clone 27 (ART-27) protein is a protein that in humans is encoded by the UXT gene.

<span class="mw-page-title-main">SPDEF</span> Protein-coding gene in the species Homo sapiens

SAM pointed domain-containing Ets transcription factor is a protein that in humans is encoded by the SPDEF gene.

<i>EHF</i> (gene) Protein-coding gene in the species Homo sapiens

ETS homologous factor is a protein that in humans is encoded by the EHF gene. This gene encodes a protein that belongs to an ETS transcription factor subfamily characterized by epithelial-specific expression (ESEs). The encoded protein acts as a transcriptional repressor and may be associated with asthma susceptibility. This protein may be involved in epithelial differentiation and carcinogenesis.

<span class="mw-page-title-main">MAGEA11</span> Protein-coding gene in humans

Melanoma-associated antigen 11 is a protein that in humans is encoded by the MAGEA11 gene. It is also involved in the androgen and progesterone receptor signaling pathways.

<span class="mw-page-title-main">NKX2-2</span> Protein-coding gene in the species Homo sapiens

Homeobox protein Nkx-2.2 is a protein that in humans is encoded by the NKX2-2 gene.

<span class="mw-page-title-main">IRX5</span> Protein-coding gene in the species Homo sapiens

Iroquois-class homeodomain protein IRX-5, also known as Iroquois homeobox protein 5, is a protein that in humans is encoded by the IRX5 gene.

<span class="mw-page-title-main">FOXA1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.

CUX1 is an animal gene. The name stands for Cut like homeobox 1. The term "cut" derives from the "cut wing" phenotype observed in a mutant of Drosophila melanogaster. In mammals, a CCAAT-displacement activity was originally described in DNA binding assays. The human gene was identified following purification of the CCAAT-displacement protein (CDP) and has been successively been called CDP, Cut-like 1 (CUTL1), CDP/Cut and finally, CUX1.. Cut homeobox genes are present in all metazoans. In mammals, CUX1 is expressed ubiquitously in all tissues. A second gene, called CUX2, is expressed primarily in neuronal cells.

<span class="mw-page-title-main">SRARP</span> Protein-coding gene in the species Homo sapiens

Steroid Receptor Associated and Regulated Protein (SRARP) in humans is a protein encoded by a gene of the same name with two exons that is located on chromosome 1p36.13. SRARP contains 169 amino acids and has a molecular weight of 17,657 Da.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000167034 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022061 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 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 (Jul 1997). "A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer". Genomics. 43 (1): 69–77. doi: 10.1006/geno.1997.4715 . PMID   9226374.
  6. "Entrez Gene: NKX3-1 NK3 transcription factor related, locus 1 (Drosophila)".
  7. "NCBI - WWW Error Blocked Diagnostic". www.ncbi.nlm.nih.gov.
  8. Gurel B, Ali TZ, Montgomery EA, Begum S, Hicks J, Goggins M, Eberhart CG, Clark DP, Bieberich CJ, Epstein JI, De Marzo AM (Aug 2010). "NKX3.1 as a marker of prostatic origin in metastatic tumors". The American Journal of Surgical Pathology. 34 (8): 1097–1105. doi:10.1097/PAS.0b013e3181e6cbf3. PMC   3072223 . PMID   20588175.
  9. Zhang Y, Fillmore RA, Zimmer WE (Mar 2008). "Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor". Experimental Biology and Medicine. 233 (3): 297–309. doi:10.3181/0709-RM-236. PMID   18296735. S2CID   9377426.
  10. Korkmaz KS, Korkmaz CG, Ragnhildstveit E, Kizildag S, Pretlow TG, Saatcioglu F (Dec 2000). "Full-length cDNA sequence and genomic organization of human NKX3A - alternative forms and regulation by both androgens and estrogens". Gene. 260 (1–2): 25–36. doi:10.1016/S0378-1119(00)00453-4. PMID   11137288.
  11. Abate-Shen C, Shen MM, Gelmann E (Jul 2008). "Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis". Differentiation; Research in Biological Diversity. 76 (6): 717–727. doi:10.1111/j.1432-0436.2008.00292.x. PMC   3683569 . PMID   18557759.
  12. Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV, Hu YP, Price SM, Abate-Shen C, Shen MM (Sep 2009). "A luminal epithelial stem cell that is a cell of origin for prostate cancer". Nature. 461 (7263): 495–500. Bibcode:2009Natur.461..495W. doi:10.1038/nature08361. PMC   2800362 . PMID   19741607.
  13. "Researchers identify protein essential for making stem cells". 9 September 2013.
  14. Kunderfranco P, Mello-Grand M, Cangemi R, Pellini S, Mensah A, Albertini V, Malek A, Chiorino G, Catapano CV, Carbone GM (2010). "ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer". PLOS ONE. 5 (5): e10547. Bibcode:2010PLoSO...510547K. doi: 10.1371/journal.pone.0010547 . PMC   2866657 . PMID   20479932.
  15. 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 (Jul 1997). "A novel human prostate-specific, androgen-regulated homeobox gene (NKX3.1) that maps to 8p21, a region frequently deleted in prostate cancer". Genomics. 43 (1): 69–77. doi: 10.1006/geno.1997.4715 . PMID   9226374.
  16. "Prostate Cancer | Prostate Cancer Information and Overview". www.cancer.org. Archived from the original on 2015-04-08. Retrieved 2015-04-23.
  17. Chuang AY, DeMarzo AM, Veltri RW, Sharma RB, Bieberich CJ, Epstein JI (Aug 2007). "Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma". The American Journal of Surgical Pathology. 31 (8): 1246–1255. doi:10.1097/PAS.0b013e31802f5d33. PMID   17667550. S2CID   11535862.
  18. Chen H, Nandi AK, Li X, Bieberich CJ (Jan 2002). "NKX-3.1 interacts with prostate-derived Ets factor and regulates the activity of the PSA promoter". Cancer Research. 62 (2): 338–40. PMID   11809674.
  19. Padmanabhan A, Gosc EB, Bieberich CJ (May 2013). "Stabilization of the prostate-specific tumor suppressor NKX3.1 by the oncogenic protein kinase Pim-1 in prostate cancer cells". Journal of Cellular Biochemistry. 114 (5): 1050–7. doi:10.1002/jcb.24444. PMID   23129228. S2CID   29814674.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.