Genomes and Genes
Gene Symbol: Nkx3-1
Description: NK3 homeobox 1
Alias: Bax, NKX3.1, NKX3A, Nkx-3.1, bagpipe, homeobox protein Nkx-3.1, Drosophila NK-3 transcription factor, locus 1, NK-3 transcription factor, locus 1, homeobox protein NK-3 homolog A
- Klezovitch O, Risk M, Coleman I, Lucas J, Null M, True L, et al. A causal role for ERG in neoplastic transformation of prostate epithelium. Proc Natl Acad Sci U S A. 2008;105:2105-10 pubmed publisher..Our data demonstrate that ERG plays an important causal role in the transformation of prostate epithelium and should be considered as a target for prevention or early therapeutic intervention. ..
- Wang X, Kruithof de Julio M, Economides K, Walker D, Yu H, Halili M, et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature. 2009;461:495-500 pubmed publisher..These observations indicate that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer. ..
- Simmons S, Horowitz J. Nkx3.1 binds and negatively regulates the transcriptional activity of Sp-family members in prostate-derived cells. Biochem J. 2006;393:397-409 pubmed..1 DNA-binding activity is itself not required. We conclude that Nkx3.1 negatively regulates Sp-mediated transcription via the tethering of histone deacetylases and/or by inhibiting the association of Sp proteins with co-activators. ..
- Song H, Zhang B, Watson M, Humphrey P, Lim H, Milbrandt J. Loss of Nkx3.1 leads to the activation of discrete downstream target genes during prostate tumorigenesis. Oncogene. 2009;28:3307-19 pubmed publisher..1 loss depend on the epithelial proliferative stage at which its expression is lost, and that alterations in the PTEN-AKT-NKX3.1 axis are important for prostate cancer initiation. ..
- Chen H, Mutton L, Prins G, Bieberich C. Distinct regulatory elements mediate the dynamic expression pattern of Nkx3.1. Dev Dyn. 2005;234:961-73 pubmed..1 cis-regulatory elements provides a unique starting point to dissect signaling pathways involved in prostate organogenesis and pathogenesis and provides a system to perturb gene expression throughout prostate development. ..
- Aytes A, Mitrofanova A, Lefebvre C, Alvarez M, Castillo Martin M, Zheng T, et al. Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell. 2014;25:638-651 pubmed publisher..Thus, genome-wide cross-species interrogation of regulatory networks represents a valuable strategy to identify causal mechanisms of human cancer. ..
- Floc h N, Kinkade C, Kobayashi T, Aytes A, Lefebvre C, Mitrofanova A, et al. Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Res. 2012;72:4483-93 pubmed publisher..Our findings suggest that dual targeting of the Akt and mTOR signaling pathways using MK-2206 and ridaforolimus (MK-8669) may be effective for treatment of CRPC, particularly for patients with deregulated Rb pathway activity. ..
- Herbrand H, Pabst O, Hill R, Arnold H. Transcription factors Nkx3.1 and Nkx3.2 (Bapx1) play an overlapping role in sclerotomal development of the mouse. Mech Dev. 2002;117:217-24 pubmed..1 contributes to the formation of the axial skeleton in addition to the Bapx1 gene. Moreover, both genes seem to collaborate in a yet unknown vital function in the mouse embryo. ..
- Aytes A, Mitrofanova A, Kinkade C, Lefebvre C, Lei M, Phelan V, et al. ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. Proc Natl Acad Sci U S A. 2013;110:E3506-15 pubmed publisher..Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer. ..
- Simons B, Hurley P, Huang Z, Ross A, Miller R, Marchionni L, et al. Wnt signaling though beta-catenin is required for prostate lineage specification. Dev Biol. 2012;371:246-55 pubmed publisher..Deletion of beta-catenin in the adult prostate did not significantly affect organ homeostasis. Collectively, these data establish that beta-catenin and Wnt signaling play key roles in prostate lineage specification and bud outgrowth. ..
- Thomsen M, Butler C, Shen M, Swain A. Sox9 is required for prostate development. Dev Biol. 2008;316:302-11 pubmed publisher..These studies imply that Sox9 is required for the early differentiation of the prostate bud epithelia. ..
- Gao H, Ouyang X, Banach Petrosky W, Borowsky A, Lin Y, Kim M, et al. A critical role for p27kip1 gene dosage in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci U S A. 2004;101:17204-9 pubmed..Our findings suggest that p27(kip1) possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression. ..
- Lei Q, Jiao J, Xin L, Chang C, Wang S, Gao J, et al. NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss. Cancer Cell. 2006;9:367-78 pubmed..1 has little effect on Pten wild-type epithelium, suggesting that PTEN plays a predominant role in PTEN-NKX3.1 interplay. Manipulating NKX3.1 expression may serve as a therapeutic strategy for treating PTEN-deficient prostate cancers. ..
- Khalili M, Mutton L, Gurel B, Hicks J, De Marzo A, Bieberich C. Loss of Nkx3.1 expression in bacterial prostatitis: a potential link between inflammation and neoplasia. Am J Pathol. 2010;176:2259-68 pubmed publisher..These observations provide a plausible mechanism whereby prostate inflammation may establish a local environment conducive to epithelial cell growth...
- Abdulkadir S, Magee J, Peters T, Kaleem Z, Naughton C, Humphrey P, et al. Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Mol Cell Biol. 2002;22:1495-503 pubmed..1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation. ..
- Tanaka M, Komuro I, Inagaki H, Jenkins N, Copeland N, Izumo S. Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands. Dev Dyn. 2000;219:248-60 pubmedNkx3.1 is a homeobox gene related to Drosophila bagpipe. Nkx3...
- Gao N, Ishii K, Mirosevich J, Kuwajima S, Oppenheimer S, Roberts R, et al. Forkhead box A1 regulates prostate ductal morphogenesis and promotes epithelial cell maturation. Development. 2005;132:3431-43 pubmed..These data indicate that Foxa1 plays a pivotal role in controlling prostate morphogenesis and cell differentiation. ..
- Banach Petrosky W, Jessen W, Ouyang X, Gao H, Rao J, Quinn J, et al. Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice. Cancer Res. 2007;67:9089-96 pubmed..We propose that exposure to reduced androgens may promote prostate tumorigenesis by selecting for molecular events that promote more aggressive, hormone-refractory tumors. ..
- Schneider A, Brand T, Zweigerdt R, Arnold H. Targeted disruption of the Nkx3.1 gene in mice results in morphogenetic defects of minor salivary glands: parallels to glandular duct morphogenesis in prostate. Mech Dev. 2000;95:163-74 pubmed..Expression in lung appeared augmented in the absence of Shh. Our results suggest that Nkx3.1 plays a unique role in regulating proliferation of glandular epithelium and in the formation of ducts in prostate and minor salivary glands. ..
- Li X, Guan B, Maghami S, Bieberich C. NKX3.1 is regulated by protein kinase CK2 in prostate tumor cells. Mol Cell Biol. 2006;26:3008-17 pubmed..1, whereas CK2alpha' liberated from the holoenzyme could not. These data establish CK2 as a regulator of NKX3.1 in prostate tumor cells and provide evidence for functionally distinct pools of CK2alpha' in LNCaP cells. ..
- Anderson P, McKissic S, Logan M, Roh M, Franco O, Wang J, et al. Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis. J Clin Invest. 2012;122:1907-19 pubmed publisher..We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis. ..
- Kim M, Cardiff R, Desai N, Banach Petrosky W, Parsons R, Shen M, et al. Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis. Proc Natl Acad Sci U S A. 2002;99:2884-9 pubmed..Our findings underscore the significance of interactions between tissue-specific regulators such as Nkx3.1 and broad-spectrum tumor suppressors such as Pten in contributing to the distinct phenotypes of different cancers. ..
- Gao H, Ouyang X, Banach Petrosky W, Shen M, Abate Shen C. Emergence of androgen independence at early stages of prostate cancer progression in Nkx3.1; Pten mice. Cancer Res. 2006;66:7929-33 pubmed
- Muhlbradt E, Asatiani E, Ortner E, Wang A, Gelmann E. NKX3.1 activates expression of insulin-like growth factor binding protein-3 to mediate insulin-like growth factor-I signaling and cell proliferation. Cancer Res. 2009;69:2615-22 pubmed publisher..Thus, there is a close relationship in vitro and in vivo between NKX3.1 and IGFBP-3. The growth-suppressive effects of NKX3.1 in prostate cells are mediated, in part, by activation of IGFBP-3 expression. ..
- Bhatia Gaur R, Donjacour A, Sciavolino P, Kim M, Desai N, Young P, et al. Roles for Nkx3.1 in prostate development and cancer. Genes Dev. 1999;13:966-77 pubmed..The Nkx3.1 mutant mice provide a unique animal model for examining the relationship between normal prostate differentiation and early stages of prostate carcinogenesis. ..
- Abate Shen C, Banach Petrosky W, Sun X, Economides K, Desai N, Gregg J, et al. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Res. 2003;63:3886-90 pubmed..We conclude that Nkx3.1(+/-); Pten(+/-) mice recapitulate key features of advanced prostate cancer and represent a useful model for investigating associated molecular mechanisms and for evaluating therapeutic approaches. ..
- Thomsen M, Ambroisine L, Wynn S, Cheah K, Foster C, Fisher G, et al. SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation. Cancer Res. 2010;70:979-87 pubmed publisher..Our findings identify SOX9 as part of a developmental pathway that is reactivated in prostate neoplasia where it promotes tumor cell proliferation. ..
- Magee J, Abdulkadir S, Milbrandt J. Haploinsufficiency at the Nkx3.1 locus. A paradigm for stochastic, dosage-sensitive gene regulation during tumor initiation. Cancer Cell. 2003;3:273-83 pubmed..Thus, loss of a single Nkx3.1 allele likely results in hyperplasia and PIN by increasing the probability of completely inactivating select Nkx3.1-regulated pathways within a subset of affected cells. ..
- Keil K, Mehta V, Abler L, Joshi P, Schmitz C, Vezina C. Visualization and quantification of mouse prostate development by in situ hybridization. Differentiation. 2012;84:232-9 pubmed publisher..We also found that Nkx3-1, Edar, and Wnt10b mark different prostatic bud regions and are likely to be useful in future studies of regional differences in prostatic bud gene expression. ..
- Zou M, Toivanen R, Mitrofanova A, Floch N, Hayati S, Sun Y, et al. Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer. Cancer Discov. 2017;7:736-749 pubmed publisher..i>Cancer Discov; 7(7); 736-49. ©2017 AACR.See related commentary by Sinha and Nelson, p. 673This article is highlighted in the In This Issue feature, p. 653. ..
- Zhang Y, Fillmore R, Zimmer W. Structural and functional analysis of domains mediating interaction between the bagpipe homologue, Nkx3.1 and serum response factor. Exp Biol Med (Maywood). 2008;233:297-309 pubmed publisher..1 and SRF that operate in concert with their respective DNA binding domains to mediate functional transcriptional synergy of these factors to regulate SMGA gene activation. ..
- Gupta A, Yu X, Case T, Paul M, Shen M, Kaestner K, et al. Mash1 expression is induced in neuroendocrine prostate cancer upon the loss of Foxa2. Prostate. 2013;73:582-9 pubmed publisher..These studies suggest that the TRAMP NE tumors can form in the absence of Foxa2 by an up regulation of Mash1. ..
- Wang J, Kobayashi T, Floc h N, Kinkade C, Aytes A, Dankort D, et al. B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer. Cancer Res. 2012;72:4765-76 pubmed..Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K ? Akt ? mTOR and ERK1/2 MAPK signaling pathways. ..
- Yoshiura K, Murray J. Sequence and chromosomal assignment of human BAPX1, a bagpipe-related gene, to 4p16.1: a candidate gene for skeletal dysplasia. Genomics. 1997;45:425-8 pubmed..They have increasingly been found to be mutated in human birth defect disorders. Sequences of two bagpipe-related genes in the mouse, Nkx-3.1 and Nkx-3.2, have already been reported. Nkx-3...
- Yoo Y, Roh M, Naseem A, Lysy B, Desouki M, Unno K, et al. Bmi1 marks distinct castration-resistant luminal progenitor cells competent for prostate regeneration and tumour initiation. Nat Commun. 2016;7:12943 pubmed publisher..These studies identify Bmi1 as a marker for a distinct population of castration-resistant luminal epithelial cells enriched in the proximal prostate that can serve as a cell of origin for prostate cancer. ..
- Kioussi C, O Connell S, St Onge L, Treier M, Gleiberman A, Gruss P, et al. Pax6 is essential for establishing ventral-dorsal cell boundaries in pituitary gland development. Proc Natl Acad Sci U S A. 1999;96:14378-82 pubmed..We suggest that the transient dorsal expression of Pax6 is essential for establishing a sharp boundary between dorsal and ventral cell types, based on the inhibition of Shh ventral signals. ..
- Takahashi Y, Takagi A, Hiraoka S, Koseki H, Kanno J, Rawls A, et al. Transcription factors Mesp2 and Paraxis have critical roles in axial musculoskeletal formation. Dev Dyn. 2007;236:1484-94 pubmed..The present data strongly suggest that patterning events by bHLH-type transcription factors have deep impacts on regional chondrogenic and myogenic differentiation of somitic cells, mainly by means of control of Pax genes. ..
- Toivanen R, Shen M. Prostate organogenesis: tissue induction, hormonal regulation and cell type specification. Development. 2017;144:1382-1398 pubmed publisher..Here, we provide a comprehensive overview of prostate development, focusing on recent findings regarding sexual dimorphism, bud induction, branching morphogenesis and cellular differentiation. ..
- Wells K, Mou C, Headon D, Tucker A. Defects and rescue of the minor salivary glands in Eda pathway mutants. Dev Biol. 2011;349:137-46 pubmed publisher..Supplementation with Fgf8 or Shh, previously reported targets of Eda signalling, leads to induction of gland like structures in a few cases, but these fail to develop into minor SGs. ..
- Tanaka M, Lyons G, Izumo S. Expression of the Nkx3.1 homobox gene during pre and postnatal development. Mech Dev. 1999;85:179-82 pubmedWe report here the expression pattern of Nkx3.1, a murine homolog of Drosophila bagpipe, in different stages of embryos and in neonates. Nkx3.1 was expressed in paraxial mesoderm at day 7.5 p.c., in the somite by day 8.0 p.c...
- Tanaka M, Kasahara H, Bartunkova S, Schinke M, Komuro I, Inagaki H, et al. Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. Dev Genet. 1998;22:239-49 pubmedIn Drosophila, dorsal mesodermal specification is regulated by the homeobox genes tinman and bagpipe. Vertebrate homologs of tinman and bagpipe have been isolated in various species...
- Klein R. The use of genetically engineered mouse models of prostate cancer for nutrition and cancer chemoprevention research. Mutat Res. 2005;576:111-9 pubmed
- Zhang H, Zheng T, Chua C, Shen M, Gelmann E. Nkx3.1 controls the DNA repair response in the mouse prostate. Prostate. 2016;76:402-8 pubmed publisher..We demonstrated that expression of Nkx3.1 influenced both the timing and magnitude of the DNA damage response in the prostate. Nkx3.1 affects the DNA damage response in the murine prostate and is haploinsufficient for this phenotype. ..
- Wu X, Xu K, Zhang L, Deng Y, Lee P, Shapiro E, et al. Differentiation of the ductal epithelium and smooth muscle in the prostate gland are regulated by the Notch/PTEN-dependent mechanism. Dev Biol. 2011;356:337-49 pubmed publisher..In addition, we found that both positive and negative modulation of Notch signaling results in abnormal organization of the prostate tissue, and can contribute to prostate disease in the adult organ. ..
- Gao H, Ouyang X, Banach Petrosky W, Gerald W, Shen M, Abate Shen C. Combinatorial activities of Akt and B-Raf/Erk signaling in a mouse model of androgen-independent prostate cancer. Proc Natl Acad Sci U S A. 2006;103:14477-82 pubmed..We propose that androgen independence emerges by means of epithelial-stromal competition, in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma. ..
- Wang Z, Mitrofanova A, Bergren S, Abate Shen C, Cardiff R, Califano A, et al. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat Cell Biol. 2013;15:274-83 pubmed publisher..Our results reveal the inherent plasticity of basal cells, and support a model in which different cells of origin generate distinct molecular subtypes of prostate cancer. ..
- Talos F, Mitrofanova A, Bergren S, Califano A, Shen M. A computational systems approach identifies synergistic specification genes that facilitate lineage conversion to prostate tissue. Nat Commun. 2017;8:14662 pubmed publisher..Thus, we describe a general strategy by which cell types and tissues can be generated even with limited knowledge of the developmental pathways required for their specification in vivo. ..
- Rodrigo I, Hill R, Balling R, Munsterberg A, Imai K. Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome. Development. 2003;130:473-82 pubmed..These results strongly suggest that Bapx1 is a direct target of Pax1 and Pax9. Together, we conclude that Pax1 and Pax9 are required and sufficient for the chondrogenic differentiation of sclerotomal cells. ..
- Kruithof de Julio M, Shibata M, Desai N, Reynon M, Halili M, Hu Y, et al. Canonical Wnt signaling regulates Nkx3.1 expression and luminal epithelial differentiation during prostate organogenesis. Dev Dyn. 2013;242:1160-71 pubmed publisher..We propose that activated canonical Wnt signals and Nkx3.1 function in a positive feedback loop to regulate prostate bud growth and luminal epithelial differentiation. ..
- Stafford D, Dichmann D, Chang J, Harland R. Deletion of the sclerotome-enriched lncRNA PEAT augments ribosomal protein expression. Proc Natl Acad Sci U S A. 2017;114:101-106 pubmed publisher..RNA-seq on PEAT mutant embryos showed that loss of PEAT modestly increases bone morphogenetic protein target gene expression and also elevates the expression of a large subset of ribosomal protein mRNAs. ..
- Francis J, Thomsen M, Taketo M, Swain A. ?-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma. PLoS Genet. 2013;9:e1003180 pubmed publisher..These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans...
- Treier M, Gleiberman A, O Connell S, Szeto D, McMahon J, McMahon A, et al. Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev. 1998;12:1691-704 pubmed
- Chua C, Shibata M, Lei M, Toivanen R, Barlow L, Bergren S, et al. Single luminal epithelial progenitors can generate prostate organoids in culture. Nat Cell Biol. 2014;16:951-61, 1-4 pubmed publisher..Finally, we provide evidence supporting the feasibility of organoid studies of human prostate tissue. Our studies underscore the progenitor properties of luminal cells, and identify in vitro approaches for studying prostate biology. ..
- Vinall R, Chen J, Hubbard N, Sulaimon S, Shen M, deVere White R, et al. Initiation of prostate cancer in mice by Tp53R270H: evidence for an alternative molecular progression. Dis Model Mech. 2012;5:914-20 pubmed publisher..Further characterization of this model, particularly in a setting of androgen deprivation, should allow further insight into the mechanisms by which the Tp53(R270H) mutation mediates CaP progression. ..
- Huang Y, Hamana T, Liu J, Wang C, An L, You P, et al. Type 2 Fibroblast Growth Factor Receptor Signaling Preserves Stemness and Prevents Differentiation of Prostate Stem Cells from the Basal Compartment. J Biol Chem. 2015;290:17753-61 pubmed publisher..In addition, ablation of Fgfr2 in P63(+) cells causes defective postnatal development of the prostate. Therefore, the data indicate that FGFR2 signaling is critical for preserving stemness and preventing differentiation of P-bSCs. ..
- Gary B, Azuero R, Mohanty G, Bell W, Eltoum I, Abdulkadir S. Interaction of Nkx3.1 and p27kip1 in prostate tumor initiation. Am J Pathol. 2004;164:1607-14 pubmed..Thus Nkx3.1 and p27kip1 regulate prostatic epithelial cell proliferation and tumor initiation by affecting both haploinsufficient and nonhaploinsufficient pathways. ..
- Iwata T, Schultz D, Hicks J, Hubbard G, Mutton L, Lotan T, et al. MYC overexpression induces prostatic intraepithelial neoplasia and loss of Nkx3.1 in mouse luminal epithelial cells. PLoS ONE. 2010;5:e9427 pubmed publisher..We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas. ..
- Nagel S, Ehrentraut S, Tomasch J, Lienenklaus S, Schneider B, Geffers R, et al. Transcriptional activation of prostate specific homeobox gene NKX3-1 in subsets of T-cell lymphoblastic leukemia (T-ALL). PLoS ONE. 2012;7:e40747 pubmed publisher..These results may contribute to the understanding of leukemic transcriptional networks underlying disturbed T-cell differentiation in T-ALL. ..
- Ju J, Maeng J, Zemedkun M, Ahronovitz N, Mack J, Ferretti J, et al. Physical and functional interactions between the prostate suppressor homeoprotein NKX3.1 and serum response factor. J Mol Biol. 2006;360:989-99 pubmed..1 and SRF was demonstrated by targeted mutagenesis of an NKX3.1 expression vector in a SMGA reporter assay. The results implicate the NKX3.1 N-terminal region in regulation of transcriptional activity of this tumor suppressor. ..
- Martinez E, Anderson P, Logan M, Abdulkadir S. Antioxidant treatment promotes prostate epithelial proliferation in Nkx3.1 mutant mice. PLoS ONE. 2012;7:e46792 pubmed publisher..Our findings provide new insight that may help explain the increased prostate cancer risk observed with vitamin E treatment in the SELECT trial and emphasize the need for preclinical studies using accurate models of cancer...