NKX2-5

Gene Summary

Gene:NKX2-5; NK2 homeobox 5
Aliases: CSX, CSX1, VSD3, CHNG5, HLHS2, NKX2E, NKX2.5, NKX4-1
Location:5q35.1
Summary:This gene encodes a homeobox-containing transcription factor. This transcription factor functions in heart formation and development. Mutations in this gene cause atrial septal defect with atrioventricular conduction defect, and also tetralogy of Fallot, which are both heart malformation diseases. Mutations in this gene can also cause congenital hypothyroidism non-goitrous type 5, a non-autoimmune condition. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:homeobox protein Nkx-2.5
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (71)
Pathways:What pathways are this gene/protein implicaed in?
Show (3)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Homeodomain Proteins
  • DNA Sequence Analysis
  • DNA Primers
  • Homeobox Protein Nkx-2.5
  • Tumor Suppressor Proteins
  • Polymerase Chain Reaction
  • Chromosome 5
  • Gene Expression
  • Loss of Heterozygosity
  • Prostate Cancer
  • Xenopus Proteins
  • Neoplasm Proteins
  • RTPCR
  • Myogenic Regulatory Factors
  • Breast Cancer
  • Cancer Gene Expression Regulation
  • CpG Islands
  • Cell Differentiation
  • Basic Helix-Loop-Helix Transcription Factors
  • Base Sequence
  • Adolescents
  • MEF2 Transcription Factors
  • Translocation
  • Adult T-Cell Leukemia-Lymphoma
  • Repressor Proteins
  • DNA Methylation
  • Leukemic Gene Expression Regulation
  • Retinoic Acid
  • Homeobox Genes
  • Chromosome 14
  • Versicans
  • Gene Silencing
  • Transcription Factors
  • Gene Expression Profiling
  • Signal Transduction
  • DNA-Binding Proteins
  • siRNA
  • Promoter Regions
  • Up-Regulation
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NKX2-5 (cancer-related)

Conti MA, Saleh AD, Brinster LR, et al.
Conditional deletion of nonmuscle myosin II-A in mouse tongue epithelium results in squamous cell carcinoma.
Sci Rep. 2015; 5:14068 [PubMed] Free Access to Full Article Related Publications
To investigate the contribution of nonmuscle myosin II-A (NM II-A) to early cardiac development we crossed Myh9 floxed mice and Nkx2.5 cre-recombinase mice. Nkx2.5 is expressed in the early heart (E7.5) and later in the tongue epithelium. Mice homozygous for deletion of NM II-A (A(Nkx)/A(Nkx)) are born at the expected ratio with normal hearts, but consistently develop an invasive squamous cell carcinoma (SCC) of the tongue (32/32 A(Nkx)/A(Nkx)) as early as E17.5. To assess reproducibility a second, independent line of Myh9 floxed mice derived from a different embryonic stem cell clone was tested. This second line also develops SCC indistinguishable from the first (15/15). In A(Nkx)/A(Nkx) mouse tongue epithelium, genetic deletion of NM II-A does not affect stabilization of TP53, unlike a previous report for SCC. We attribute the consistent, early formation of SCC with high penetrance to the role of NM II in maintaining mitotic stability during karyokinesis.

Wang L, Huang J, Jiang M, et al.
CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) by biocomputation.
Cell Biochem Biophys. 2014; 70(2):1011-6 [PubMed] Related Publications
We data-analyzed and constructed the high-expression CAMK1 phosphoinositide signal-mediated protein sorting and transport network in human hepatocellular carcinoma (HCC) compared with low-expression (fold change ≥ 2) no-tumor hepatitis/cirrhotic tissues (HBV or HCV infection) in GEO data set, using integration of gene regulatory network inference method with gene ontology (GO). Our result showed that CAMK1 transport subnetwork upstream KCNQ3, LCN2, NKX2_5, NUP62, SORT1, STX1A activated CAMK1, and downstream CAMK1-activated AFP, ENAH, KPNA2, SLC4A3; CAMK1 signal subnetwork upstream BRCA1, DKK1, GPSM2, LEF1, NR5A1, NUP62, SORT1, SSTR5, TBL3 activated CAMK1, and downstream CAMK1-activated MAP2K6, SFRP4, SSTR5, TSHB, UBE2C in HCC. We proposed that CAMK1 activated network enhanced endosome to lysosome transport, endosome transport via multivesicular body sorting pathway, Golgi to endosome transport, intracellular protein transmembrane transport, intracellular protein transport, ion transport, mRNA transport, plasma membrane to endosome transport, potassium ion transport, protein transport, vesicle-mediated transport, anion transport, intracellular transport, androgen receptor signaling pathway, cell surface receptor-linked signal transduction, hormone-mediated signaling, induction of apoptosis by extracellular signals, signal transduction by p53 class mediator resulting in transcription of p21 class mediator, signal transduction resulting in induction of apoptosis, phosphoinositide-mediated signaling, Wnt receptor signaling pathway, as a result of inducing phosphoinositide signal-mediated protein sorting, and transport in HCC. Our hypothesis was verified by CAMK1 functional regulation subnetwork containing positive regulation of calcium ion transport via voltage gated calcium channel, cell proliferation, DNA repair, exocytosis, I-kappaB kinase/NF-kappaB cascade, immunoglobulin-mediated immune response, mast cell activation, natural killer cell-mediated cytotoxicity directed against tumor cell target, protein ubiquitination, sodium ion transport, survival gene product activity, T cell-mediated cytotoxicity, transcription, transcription from RNA polymerase II promoter, transcription initiation from RNA polymerase II promoter, transcription via serum response element binding, exit from mitosis, ubiquitin ligase activity during mitotic cell cycle, regulation of angiogenesis, apoptosis, cell growth, cell proliferation, cyclin-dependent protein kinase activity, gene expression, insulin secretion, steroid biosynthesis, transcription from RNA polymerase II promoter, transcription from RNA polymerase III promoter, cell cycle, cell migration, DNA recombination, and protein metabolism; also by CAMK1 negative functional regulation subnetwork including negative regulation of apoptosis, cell proliferation, centriole replication, fatty acid biosynthesis, lipoprotein lipase activity, MAPK activity, progression through cell cycle, transcription, transcription from RNA polymerase II promoter, cell growth, phosphorylation, and ubiquitin ligase activity during mitotic cell cycle in HCC.

Nagel S, Ehrentraut S, Tomasch J, et al.
Ectopic expression of homeobox gene NKX2-1 in diffuse large B-cell lymphoma is mediated by aberrant chromatin modifications.
PLoS One. 2013; 8(4):e61447 [PubMed] Free Access to Full Article Related Publications
Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2-1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies.

Vasiljević N, Wu K, Brentnall AR, et al.
Absolute quantitation of DNA methylation of 28 candidate genes in prostate cancer using pyrosequencing.
Dis Markers. 2011; 30(4):151-61 [PubMed] Free Access to Full Article Related Publications
Aberrant DNA methylation plays a pivotal role in carcinogenesis and its mapping is likely to provide biomarkers for improved diagnostic and risk assessment in prostate cancer (PCa). We quantified and compared absolute methylation levels among 28 candidate genes in 48 PCa and 29 benign prostate hyperplasia (BPH) samples using the pyrosequencing (PSQ) method to identify genes with diagnostic and prognostic potential. RARB, HIN1, BCL2, GSTP1, CCND2, EGFR5, APC, RASSF1A, MDR1, NKX2-5, CDH13, DPYS, PTGS2, EDNRB, MAL, PDLIM4, HLAa, ESR1 and TIG1 were highly methylated in PCa compared to BPH (p < 0.001), while SERPINB5, CDH1, TWIST1, DAPK1, THRB, MCAM, SLIT2, CDKN2a and SFN were not. RARB methylation above 21% completely distinguished PCa Separation based on methylation level of SFN, SLIT2 and SERPINB5 distinguished low and high Gleason score cancers, e.g. SFN and SERPINB5 together correctly classified 81% and 77% of high and low Gleason score cancers respectively. Several genes including CDH1 previously reported as methylation markers in PCa were not confirmed in our study. Increasing age was positively associated with gene methylation (p < 0.0001).Accurate quantitative measurement of gene methylation in PCa appears promising and further validation of genes like RARB, HIN1, BCL2, APC and GSTP1 is warranted for diagnostic potential and SFN, SLIT2 and SERPINB5 for prognostic potential.

Bell A, Bell D, Weber RS, El-Naggar AK
CpG island methylation profiling in human salivary gland adenoid cystic carcinoma.
Cancer. 2011; 117(13):2898-909 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: DNA methylation is a fundamental epigenetic event associated with physiologic and pathologic conditions, including cancer. Hypermethylation of CpG islands at active gene promoters leads to transcriptional repression, whereas hypomethylation is associated with gene overexpression. The aim of this study was to identify genes in adenoid cystic carcinoma (ACC) of salivary gland strongly deregulated by epigenetic CpG island methylation, to validate selected genes by conventional techniques, and to correlate the findings with clinicopathologic factors.
METHODS: The authors analyzed 16 matched normal and tumor tissues for aberrant DNA methylation using the methylated CpG island amplification and microarray method and the pyrosequencing technique.
RESULTS: Microarray analysis showed hypomethylation in 7 and hypermethylation in 32 CpG islands. Hypomethylation was identified in CpG islands near FBXO17, PHKG1, LOXL1, DOCK1, and PARVG. Hypermethylation was identified near genes encoding predominantly transcription factors (EN1, FOXE1, GBX2, FOXL1, TBX4, MEIS1, LBX2, NR2F2, POU3F3, IRX3, TFAP2C, NKX2-4, PITX1, NKX2-5), and 13 genes with different functions (MT1H, EPHX3, AQPEP, BCL2L11, SLC35D3, S1PR5, PNLIPRP1, CLIC6, RASAL, XRN2, GSTM5, FNDC1, INSRR). Four CpG islands by EN1, FOXE1, TBX4, and PITX1 were validated by pyrosequencing.
CONCLUSIONS: The highly methylated genes in tumor versus normal tissue are linked to developmental, apoptotic, and other fundamental cellular pathways, suggesting that down-regulation of these genes is associated with ACC development and progression. With EN1 hypermethylation showing potential as a possible biomarker for ACC in salivary gland, the biological and therapeutic implications of these findings require further preclinical investigations.

Nagel S, Venturini L, Meyer C, et al.
Transcriptional deregulation of oncogenic myocyte enhancer factor 2C in T-cell acute lymphoblastic leukemia.
Leuk Lymphoma. 2011; 52(2):290-7 [PubMed] Related Publications
Myocyte enhancer factor 2C (MEF2C) encodes a transcription factor which is ectopically expressed in T-cell acute lymphoblastic leukemia (T-ALL) cell lines, deregulated directly by ectopically expressed homeodomain protein NKX2-5 or by loss of promoter regions via del(5)(q14). Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop-helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5. HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. Lacking comma: Chromosomal deletion of the STAT5 binding site in LOUCY cells reduced protein levels of STAT5 in some MEF2C-positve T-ALL cell lines, and the presence of inhibitory IL7-JAK-STAT5 signaling highlighted the repressive impact of this factor in MEF2C regulation. Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling.

Ylipää A, Yli-Harja O, Zhang W, Nykter M
A systems biological approach to identify key transcription factors and their genomic neighborhoods in human sarcomas.
Chin J Cancer. 2011; 30(1):27-40 [PubMed] Free Access to Full Article Related Publications
Identification of genetic signatures is the main objective for many computational oncology studies. The signature usually consists of numerous genes that are differentially expressed between two clinically distinct groups of samples, such as tumor subtypes. Prospectively, many signatures have been found to generalize poorly to other datasets and, thus, have rarely been accepted into clinical use. Recognizing the limited success of traditionally generated signatures, we developed a systems biology-based framework for robust identification of key transcription factors and their genomic regulatory neighborhoods. Application of the framework to study the differences between gastrointestinal stromal tumor (GIST) and leiomyosarcoma (LMS) resulted in the identification of nine transcription factors (SRF, NKX2-5, CCDC6, LEF1, VDR, ZNF250, TRIM63, MAF, and MYC). Functional annotations of the obtained neighborhoods identified the biological processes which the key transcription factors regulate differently between the tumor types. Analyzing the differences in the expression patterns using our approach resulted in a more robust genetic signature and more biological insight into the diseases compared to a traditional genetic signature.

Cheol Kim D, Thorat MA, Lee MR, et al.
Quantitative DNA methylation and recurrence of breast cancer: a study of 30 candidate genes.
Cancer Biomark. 2012; 11(2-3):75-88 [PubMed] Related Publications
BACKGROUND: The need for new prognostic factors in breast cancer is ever increasing as breast cancer management evolves. Aberrant DNA methylation plays a pivotal role in cancer development and progression; DNA methylation-based biomarkers may provide independent prognostic information. We used pyrosequencing to investigate the prognostic potential of quantitative DNA methylation of a large set of candidate genes in a Korean single-institution series of operable breast cancer.
METHODS: Absolute DNA methylation in 20 candidate genes from an initial set of 30 genes was measured by pyrosequencing of bisulfite converted DNA in 121 fresh frozen breast cancer cases. Survival analyses used continuous and categorized (quintile-based) gene methylation data with time to recurrence (TTR) as an endpoint. Prognostic abilities of gene-only and risk-score models were explored.
RESULTS: Median follow-up was 5.1 years; 25 recurrences (21%) were observed. Nodal status, methylation of TWIST1, SLIT2 (both as continuous and categorized variables) and APC, HLA-A, NKX2-5, SERPINB5, SFN (as categorized variables) were significantly prognostic; grade showed a prognostic trend. A multivariate model containing nodal status, grade and TWIST1 was a best fit (p< 0.001) in stepwise regression; risk-score based on this model separated patients into 3 distinct risk-groups (p< 0.001). A gene-only model based on TWIST1 and SFN also classified patients into distinct risk-groups (p=0.009).
CONCLUSIONS: This study shows that accurate quantitative measurement of DNA methylation by pyrosequencing identifies a small set of genes with independent prognostic potential in breast cancer. These genes complement the current clinico-pathological prognostic factors and appear to be potential biomarkers that warrant further validation.

Hou D, Guan Y, Liu J, et al.
Cloning and characterization of the NPCEDRG gene promoter.
Mol Cell Biochem. 2011; 346(1-2):1-10 [PubMed] Related Publications
NPCEDRG is a novel tumor suppressive gene that localizes to 3p21.3, a chromosomal region frequently associated with loss of heterozygosity (LOH) in a number of malignancies including nasopharyngeal carcinoma (NPC). Its transcriptional down-expression has been shown in the cell lines and primary tumor tissues of NPC. Reintroduction of NPCEDRG into CNE2, a cell line derived from NPC, was effective to induce cell differentiation, control cell growth, and regulate the cell cycle. Little is known about the transcriptional mechanisms controlling NPCEDRG gene expression. In this article, we describe the NPCEDRG gene structure and the transcriptional expression of NPCEDRG; we found that NPCEDRG was expressed weakly in most of NPC cell lines. Using 5' rapid amplification of complementary DNA ends (5'-RACEs), we found that the NPCEDRG gene has several transcription start sites (TSSs) due to the existence of alternatively spliced variants, and the specific TSS of NPCEDRG was located -25 nucleotides upstream of the translation start site. We amend that Human NPCEDRG CDS containing 516 bp but not the 510 bp reported previously. To characterize the NPCEDRG promoter, transient luciferase and/or EGFP reporter assay were carried out with the constructs including various lengths of the 5' flanking region of the NPCEDRG gene. The results demonstrated that the basal promoter is located at the region from -215 to -8 nucleotides, and the optimal promoter is located at the region from -625 to -8 nucleotides upstream of the translation start site. In silico analysis suggested that the promoter region contained potential binding sites for SP1, c-Myb, AREB6, Nkx2-5, and so on. These results provide important clues to elucidate the regulation of NPCEDRG gene expression and function. Further studies are apparently required for the identification of the transcription factors, essential for NPCEDRG expression, which would lead to better understanding of the molecular mechanism of NPCEDRG expression in nasopharyngeal epithelial cells.

Kwabi-Addo B, Wang S, Chung W, et al.
Identification of differentially methylated genes in normal prostate tissues from African American and Caucasian men.
Clin Cancer Res. 2010; 16(14):3539-47 [PubMed] Related Publications
PURPOSE: Aberrant DNA methylation changes are common somatic alterations in prostate carcinogenesis. We examined the methylation status of six genes in prostate tissue specimens from African American (AA) and Caucasian (Cau) males.
EXPERIMENTAL DESIGN: We used pyrosequencing to quantitatively measure the methylation status of GSTP1, AR, RARbeta2, SPARC, TIMP3, and NKX2-5. Real-time PCR was used to determine gene expression, and gene reactivation was analyzed by 5-aza-2'-deoxycytidine and/or trichostatin A treatment.
RESULTS: Statistical analysis showed significantly higher methylation in the prostate cancer tissue samples in comparison with matched normal samples for GSTP1 (P = 0.0001 for AA; P = 0.0008 for Cau), RARbeta2 (P < 0.001 for AA and Cau), SPARC (P < 0.0001 for AA and Cau), TIMP3 (P < 0.0001 for AA and Cau), and NKX2-5 (P < 0.0001 for AA; P = 0.003 for Cau). Overall, we observed significant differences (P < 0.05) in the methylation level for all genes, except GSTP1, in the AA samples in comparison with the Cau samples. Furthermore, regression analysis revealed significantly higher methylation for NKX2-5 (P = 0.008) and TIMP3 (P = 0.039) in normal prostate tissue samples from AA in comparison with Cau, and a statistically significant association of methylation with age for NKX2-5 (P = 0.03) after adjusting for race.
CONCLUSION: Our findings show higher methylation of several genes in prostate tissue samples from AA in comparison with Cau and may potentially contribute to the racial differences that are observed in prostate cancer pathogenesis.

Mossner M, Hopfer O, Nowak D, et al.
Detection of differential mitotic cell age in bone marrow CD34(+) cells from patients with myelodysplastic syndrome and acute leukemia by analysis of an epigenetic molecular clock DNA signature.
Exp Hematol. 2010; 38(8):661-5 [PubMed] Related Publications
OBJECTIVE: Recently, the "epigenetic molecular clock hypothesis" linked increasing DNA methylation in a distinct CpG island in the cardiac-specific homeobox gene (CSX) gene to relative mitotic cell age. To determine mitotic cell age in hematopoietic cells of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients, we assessed differential CSX methylation patterns in these diseases vs age-adjusted healthy controls.
MATERIALS AND METHODS: We performed bisulfite pyrosequencing to analyze CSX methylation in CD34(+) and bone marrow (BM) cells from 53 MDS, 62 AML, 77 ALL patients, and 37 controls.
RESULTS: Analysis of MDS CD34(+) and BM cells revealed significantly increasing methylation of CSX in controls < MDS low-risk < MDS high-risk < AML. Furthermore, increased differences of CSX methylation between the CD34(+) vs the unselected BM compartment were detected in matched MDS low-risk but not high-risk and AML samples. ALL samples displayed highly elevated CSX methylation levels as compared to controls.
CONCLUSIONS: Assessment of mitotic cell age by CSX methylation analysis could reveal novel insights into the distinct progression of hematologic diseases.

Nagel S, Venturini L, Przybylski GK, et al.
NK-like homeodomain proteins activate NOTCH3-signaling in leukemic T-cells.
BMC Cancer. 2009; 9:371 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Homeodomain proteins control fundamental cellular processes in development and in cancer if deregulated. Three members of the NK-like subfamily of homeobox genes (NKLs), TLX1, TLX3 and NKX2-5, are implicated in T-cell acute lymphoblastic leukemia (T-ALL). They are activated by particular chromosomal aberrations. However, their precise function in leukemogenesis is still unclear. Here we screened further NKLs in 24 T-ALL cell lines and identified the common expression of MSX2. The subsequent aim of this study was to analyze the role of MSX2 in T-cell differentiation which may be disturbed by oncogenic NKLs.
METHODS: Specific gene activity was examined by quantitative real-time PCR, and globally by expression profiling. Proteins were analyzed by western blot, immuno-cytology and immuno-precipitation. For overexpression studies cell lines were transduced by lentiviruses.
RESULTS: Quantification of MSX2 mRNA in primary hematopoietic cells demonstrated higher levels in CD34+ stem cells as compared to peripheral blood cells and mature CD3+ T-cells. Furthermore, analysis of MSX2 expression levels in T-cell lines after treatment with core thymic factors confirmed their involvement in regulation. These results indicated that MSX2 represents an hematopoietic NKL family member which is downregulated during T-cell development and may functionally substituted by oncogenic NKLs. For functional analysis JURKAT cells were lentivirally transduced, overexpressing either MSX2 or oncogenic TLX1 and NKX2-5, respectively. These cells displayed transcriptional activation of NOTCH3-signaling, including NOTCH3 and HEY1 as analyzed by gene expression profiling and quantitative RT-PCR, and consistently attenuated sensitivity to gamma-secretase inhibitor as analyzed by MTT-assays. Furthermore, in addition to MSX2, both TLX1 and NKX2-5 proteins interacted with NOTCH-pathway repressors, SPEN/MINT/SHARP and TLE1/GRG1, representing a potential mechanism for (de)regulation. Finally, elevated expression of NOTCH3 and HEY1 was detected in primary TLX1/3 positive T-ALL cells corresponding to the cell line data.
CONCLUSION: Identification and analysis of MSX2 in hematopoietic cells implicates a modulatory role via NOTCH3-signaling in early T-cell differentiation. Our data suggest that reduction of NOTCH3-signaling by physiological downregulation of MSX2 expression during T-cell development is abrogated by ectopic expression of oncogenic NKLs, substituting MSX2 function.

Nagel S, Venturini L, Meyer C, et al.
Multiple mechanisms induce ectopic expression of LYL1 in subsets of T-ALL cell lines.
Leuk Res. 2010; 34(4):521-8 [PubMed] Related Publications
Basic helix-loop-helix (bHLH) transcription factors are essential for lymphocytic differentiation. Here, we have analyzed the complete bHLH family in T-cell acute lymphoblastic leukemia cell lines by expression profiling. Differential expression was detected for BHLHB2, HES1, HES4, HEY1, ID1, ID2, ID3, LYL1 and TAL1, highlighting dysregulation of family members with inhibitory activity. Subsequently we focused on the mechanisms responsible for aberrant expression of LYL1 in comparison to TAL1. Quantitative genomic PCR indicated microdeletions upstream of both, TAL1 and LYL1, targeting STIL/SIL and TRMT1, respectively. Additionally, one LYL1-expressing cell line exhibited amplification of TRMT1. While deletion of STIL correlated with expression of the STIL-TAL1 fusion transcript, no TRMT-LYL1 fusion transcripts were detected in parallel with genomic rearrangements thereof. Sequence analysis of the LYL1 promoter region revealed potential binding sites for transcription factors HOXA10, LMO2 and NKX2-5. Overexpression analysis, reporter gene assays and chromatin immuno-precipitation confirmed their activating impact on LYL1 expression. In conclusion, we identified multiple mechanisms which activate LYL1 in leukemic cells, including structural genomic alterations, namely microdeletion or amplification, together with the involvement of prominent oncogenic transcription factors.

Qiu Y, Michalak M
Transcriptional control of the calreticulin gene in health and disease.
Int J Biochem Cell Biol. 2009; 41(3):531-8 [PubMed] Related Publications
Calreticulin is a multifunctional Ca(2+) binding chaperone in the endoplasmic reticulum and expression of the protein is tightly regulated at the transcriptional level. There are two calreticulin genes, named calreticulin-1 and calreticulin-2 gene. The calreticulin-1 promoter contains a number of putative binding sites for transcription factors including tissue specific factors. Direct regulation of the calreticulin-1 promoter by several of these factors has been confirmed experimentally including Nkx2.5, MEF2C, GATA6, PPAR, COUP-TF1 and Evi-1 factors. Studies on calreticulin-deficient mice and transgenic animal models indicate that calreticulin is critical for cardiac development and that expression of the protein must be tightly regulated during cardiogenesis. Moreover, differential expression of calreticulin has been associated with several diseases, including neurodegenerative problems, cancers, autoimmune diseases and wound healing. Understanding the mechanisms responsible for the regulation of expression of calreticulin may contribute to the treatment of many diverse diseases.

Chung W, Kwabi-Addo B, Ittmann M, et al.
Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling.
PLoS One. 2008; 3(4):e2079 [PubMed] Free Access to Full Article Related Publications
DNA hypermethylation is a common epigenetic abnormality in cancer and may serve as a useful marker to clone cancer-related genes as well as a marker of clinical disease activity. To identify CpG islands methylated in prostate cancer, we used methylated CpG island amplification (MCA) coupled with representational difference analysis (RDA) on prostate cancer cell lines. We isolated 34 clones that corresponded to promoter CpG islands, including 5 reported targets of hypermethylation in cancer. We confirmed the data for 17 CpG islands by COBRA and/or pyrosequencing. All 17 genes were methylated in at least 2 cell lines of a 21-cancer cell line panel containing prostate cancer, colon cancer, leukemia, and breast cancer. Based on methylation in primary tumors compared to normal adjacent tissues, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS and NSE1 are candidate biomarkers for prostate cancer (methylation range 50%-85%). The combination of NSE1 or SPOCK2 hypermethylation showed a sensitivity of 80% and specificity of 95% in differentiating cancer from normal. Similarly NKX2-5, SPOCK2, SLC16A12, DPYS and GALR2 are candidate biomarkers for colon cancer (methylation range 60%-95%) and GALR2 hypermethylation showed a sensitivity of 85% and specificity of 95%. Finally, SLC16A12, GALR2, TOX, SPOCK2, EGFR5 and DPYS are candidate biomarkers for breast cancer (methylation range 33%-79%) with the combination of EGFR5 or TOX hypermethylation showing a sensitivity of 92% and specificity of 92%. Expression analysis for eight genes that had the most hypermethylation confirmed the methylation associated silencing and reactivation with 5-aza-2'-deoxycytidine treatment. Our data identify new targets of transcriptional silencing in cancer, and provide new biomarkers that could be useful in screening for prostate cancer and other cancers.

Nagel S, Meyer C, Quentmeier H, et al.
MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines.
Leukemia. 2008; 22(3):600-7 [PubMed] Related Publications
In T-cell acute lymphoblastic leukemia (T-ALL) the cardiac homeobox gene NKX2-5 (at 5q35) is variously deregulated by regulatory elements coordinating with BCL11B (at 14q32.2), or the T-cell receptor gene TRD (at 14q11.2), respectively. NKX2-5 is normally expressed in developing spleen and heart, regulating fundamental processes, including differentiation and survival. In this study we investigated whether NKX2-5 expression in T-ALL cell lines reactivates these embryonal pathways contributing to leukemogenesis. Among 18 known targets analyzed, we identified three genes regulated by NKX2-5 in T-ALL cells, including myocyte enhancer factor 2C (MEF2C). Knockdown and overexpression assays confirmed MEF2C activation by NKX2-5 at both the RNA and protein levels. Direct interactions between NKX2-5 and GATA3 as indicated by co-immunoprecipitation data may contribute to MEF2C regulation. In T-ALL cell lines LOUCY and RPMI-8402 MEF2C expression was correlated with a 5q14 deletion, encompassing noncoding proximal gene regions. Fusion constructs with green fluorescent protein permitted subcellular detection of MEF2C protein in nuclear speckles interpretable as repression complexes. MEF2C consistently inhibits expression of NR4A1/NUR77, which regulates apoptosis via BCL2 transformation. Taken together, our data identify distinct mechanisms underlying ectopic MEF2C expression in T-ALL, either as a downstream target of NKX2-5, or via chromosomal aberrations deleting proximal gene regions.

Chen Y, Yuen WH, Fu J, et al.
The mitochondrial respiratory chain controls intracellular calcium signaling and NFAT activity essential for heart formation in Xenopus laevis.
Mol Cell Biol. 2007; 27(18):6420-32 [PubMed] Free Access to Full Article Related Publications
The mitochondrial respiratory chain (MRC) plays crucial roles in cellular energy production. However, its function in early embryonic development remains largely unknown. To address this issue, GRIM-19, a newly identified MRC complex I subunit, was knocked down in Xenopus laevis embryos. A severe deficiency in heart formation was observed, and the deficiency could be rescued by reintroducing human GRIM-19 mRNA. The mechanism involved was further investigated. We found that the activity of NFAT, a transcription factor family that contributes to early organ development, was downregulated in GRIM-19 knockdown embryos. Furthermore, the expression of a constitutively active form of mouse NFATc4 in these embryos rescued the heart developmental defects. NFAT activity is controlled by a calcium-dependent protein phosphatase, calcineurin, which suggests that calcium signaling may be disrupted by GRIM-19 knockdown. Indeed, both the calcium response and calcium-induced NFAT activity were impaired in the GRIM-19 or NDUFS3 (another complex I subunit) knockdown cell lines. We also showed that NFAT can rescue expression of Nkx2.5, which is one of the key genes for early heart development. Our data demonstrated the essential role of MRC in heart formation and revealed the signal transduction and gene expression cascade involved in this process.

Kwabi-Addo B, Chung W, Shen L, et al.
Age-related DNA methylation changes in normal human prostate tissues.
Clin Cancer Res. 2007; 13(13):3796-802 [PubMed] Related Publications
PURPOSE: Prostate cancer is a leading cause of cancer death among the aging male population but the mechanism underlying this association is unclear. Aberrant methylation of promoter CpG islands is associated with silencing of genes and age-dependent methylation of several genes has been proposed as a risk factor for sporadic cancer. We examined the extent of gene methylation in pathologically normal human prostate as a function of age.
EXPERIMENTAL DESIGN: We used pyrosequencing to quantitatively analyze the methylation status of nine CpG islands in normal prostate tissue DNA from 45 organ donors and 45 patients who had undergone cystoprostatectomy for bladder cancer. We also analyzed 12 pairs of matched benign and prostate cancer tissue DNA from patients with prostate cancer.
RESULTS: Linear regression analysis revealed a significant increase in promoter methylation levels correlating with age for CpG islands at RARbeta2 (r = 0.4; P < 0.0001), RASSF1A (r = 0.27; P = 0.01), GSTP1 (r = 0.59; P < 0.0001), NKX2-5 (r = 0.27; P = 0.008), and ESR1 (r = 0.244; P = 0.023) in the normal prostate tissue samples studied. A calculated average methylation (z score) at all nine CpG loci analyzed in the normal prostate tissues showed a strong correlation with age (r = 0.6; P < 0.001). Comparison of the methylation level for the matched benign and prostate cancer tissues from individual patients with prostate cancer showed significantly higher methylation in the prostate cancer tissue samples for RARbeta2 (P < 0.001), RASSF1A (P = 0.005), GSTP1 (P < 0.001), NKX2-5 (P = 0.003), ESR1 (P = 0.016), and CLSTN1 (P = 0.01).
CONCLUSIONS: Our findings show aberrant hypermethylation as a function of age in the normal prostate tissues. Such age-related methylation may precede and predispose to full-blown malignancy.

Chen Y, Pacyna-Gengelbach M, Deutschmann N, et al.
Homeobox gene HOP has a potential tumor suppressive activity in human lung cancer.
Int J Cancer. 2007; 121(5):1021-7 [PubMed] Related Publications
The homeobox containing gene HOP (Homeodomain Only Protein) was identified in the developing heart and lung where it functions downstream of Nkx2.5 and Nkx2.1 to modulate cardiac and lung gene expression. Previously, we found that HOP was downregulated in lung cancer. In this study, we constructed an expression vector containing the full-length cDNA of HOP and transfected it into a lung cancer cell line H2170. Stable transfection led to an increased expression of HOP confirmed by Northern blot analysis. HOP positive transfectants remarkably reduced the growth rate and the ability of anchorage-independent growth in soft agar, and moreover suppressed the tumor formation in nude mice compared to controls. Transient transfection of Nkx2.1 into H2170 resulted in the overexpression of HOP, and correspondingly, siRNA silencing of Nkx2.1 reduced the expression of HOP in lung cancer cells. Treatment with a differentiation modulating agent 5-bromodeoxyuridine (BrdU) led to restoration of HOP expression in a small cell lung cancer cell line H526. In 29 paired primary lung tumor samples, loss of heterozygosity (LOH) analysis was performed by using the 3 microsatellite markers D4S189, D4S231 and D4S392 around the region of chromosome 4q12 where HOP locates. LOH was only found in 4 out 23 cases (17.4%) indicating that allelic loss is a rare genetic event not responsible for the downregulation of HOP in lung cancer. Taken together, our data suggest that HOP is a potential tumor suppressor possibly involved in lung cancer differentiation, and functions downstream of Nkx2.1.

Nagel S, Scherr M, Kel A, et al.
Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3'-BCL11B enhancers and coregulation by PU.1 and HMGA1.
Cancer Res. 2007; 67(4):1461-71 [PubMed] Related Publications
In T-cell acute lymphoblastic leukemia, alternative t(5;14)(q35;q32.2) forms effect dysregulation of either TLX3 or NKX2-5 homeobox genes at 5q35 by juxtaposition with 14q32.2 breakpoints dispersed across the BCL11B downstream genomic desert. Leukemic gene dysregulation by t(5;14) was investigated by DNA inhibitory treatments with 26-mer double-stranded DNA oligonucleotides directed against candidate enhancers at, or near, orphan T-cell DNase I hypersensitive sites located between 3'-BCL11B and VRK1. NKX2-5 down-regulation in t(5;14) PEER cells was almost entirely restricted to DNA inhibitory treatment targeting enhancers within the distal breakpoint cluster region and was dose and sequence dependent, whereas enhancers near 3'-BCL11B regulated that gene only. Chromatin immunoprecipitation assays showed that the four most effectual NKX2-5 ectopic enhancers were hyperacetylated. These enhancers clustered approximately 1 Mbp downstream of BCL11B, within a region displaying multiple regulatory stigmata, including a TCRA enhancer motif, deep sequence conservation, and tight nuclear matrix attachment relaxed by trichostatin A treatment. Intriguingly, although TLX3/NKX2-5 promoter/exon 1 regions were hypoacetylated, their expression was trichostatin A sensitive, implying extrinsic regulation by factor(s) under acetylation control. Knockdown of PU.1, known to be trichostatin A responsive and which potentially binds TLX3/NKX2-5 promoters, effected down-regulation of both homeobox genes. Moreover, genomic analysis showed preferential enrichment near ectopic enhancers of binding sites for the PU.1 cofactor HMGA1, the knockdown of which also inhibited NKX2-5. We suggest that HMGA1 and PU.1 coregulate ectopic homeobox gene expression in t(5;14) T-cell acute lymphoblastic leukemia by interactions mediated at the nuclear matrix. Our data document homeobox gene dysregulation by a novel regulatory region at 3'-BCL11B responsive to histone deacetylase inhibition and highlight a novel class of potential therapeutic target amid noncoding DNA.

Przybylski GK, Dik WA, Grabarczyk P, et al.
The effect of a novel recombination between the homeobox gene NKX2-5 and the TRD locus in T-cell acute lymphoblastic leukemia on activation of the NKX2-5 gene.
Haematologica. 2006; 91(3):317-21 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: The NK-like homeobox gene (NKX2-5/CSX) plays a crucial role in cardiac development but is not normally expressed in hematopoietic cells. Here, we describe for the first time a fusion between NKX2-5 and the T-cell receptor delta locus (TRD) resulting in NKX2-5 activation in a case of T-cell acute lymphoblastic leukemia (T-ALL).
DESIGN AND METHODS: Genomic DNA from a T-ALL patient with an atypical rearrangement, detected by Southern blotting, was analyzed by ligation-mediated polymerase chain reaction (PCR) with TRD-specific primers. Expression of NKX2-5 was analyzed by real-time quantitative PCR in the T-ALL case with the NKX2-5-TRD rearrangement, 18 other cases of T-ALL, three T-ALL derived cell lines, two non-hematopoietic cell lines, peripheral blood mononuclear cells from six healthy individuals and sorted thymocyte subsets.
RESULTS: Sequence analysis of ligation-mediated PCR products revealed a novel rearrangement between the third diversity segment of the TRD locus (TRDD3) and a region on chromosome 5q35.1 located 32 kb downstream of the NKX2-5/CSX gene. As a result of this recombination NKX2-5 was placed under influence of the TRD enhancer, resulting in strong ectopic NKX2-5 expression. High NKX2-5 expression was also found in the T-cell lines PEER and CCRF-CEM, which harbor an NKX2-5-BCL11B rearrangement, and in the embryonic kidney cell line 293. NKX2-5 was not expressed in any of the major thymocyte subsets, in normal peripheral blood mononuclear cells, or in the majority (17/18) of the other cases of T-ALL.
INTERPRETATION AND CONCLUSIONS: Our finding of overexpression of yet another homeobox gene in T-ALL further supports the hypothesis that homeobox genes play an important role in malignant transformation of particular types of T-ALL.

Katoh M, Katoh M
Comparative genomics on mammalian Fgf3-Fgf4 locus.
Int J Oncol. 2005; 27(1):281-5 [PubMed] Related Publications
The CCND1-ORAOV1-FGF19-FGF4-FGF3-TMEM16A-FADD-PPFIA1-CTTN (EMS1) locus at human chromosome 11q13.3 is amplified in head and neck tumors, esophageal cancer, Kaposi's sarcoma, bladder tumors, breast cancer, and liver cancer. Fgf4 mRNA is expressed in embryonic stem (ES) cells depending on Sox2 and Pou5f1 (Oct3/Oct4) transcription factors, and in myotomes and limb bud AER depending on MyoD (or Myf5) and GATA transcription factors. Here, rat Fgf3 and Fgf4 complete coding sequences were determined by using bioinformatics. Multiple errors, including one-base insertion and 22-base deletion, were identified within the coding region of rat Fgf4 RefSeq (NM_053809.1 or AB079673.1). Rat Fgf3 and Fgf4 genes, consisting of three exons, were clustered in tail-to-head manner with an interval of about 16 kb. CUTL1 (CCAAT-displacement protein, CDP) and NKX2-5 binding sites and TATA box within 5'-flanking promoter region were conserved among human, rat and mouse Fgf3 orthologs. MYOD and MYOG (Myogenin) binding sites and TATA box within 5'-flanking promoter region as well as GATA, MYOD, SOX2 and POU5F1 binding sites within exon 3 were conserved among mammalian Fgf4 orthologs. Human FGF3 and FGF4 genes were clustered in tail-to-head manner with an interval of about 35 kb. Major repetitive sequence (FGF34Rep1) and minor repetitive sequence (FGF34Rep2) were identified within human FGF3-FGF4 gene cluster. FGF34Rep1 were clustered within the FGF3-FGF4 locus as well as around the IL28RA locus (1p36.11) and the NFAM1 locus (22q13.2). FGF34Rep2 was characterized by the CCA(T/C) repeats. This is the first report on comparative genomics analyses on the Fgf3-Fgf4 locus within human, rat and mouse genomes.

Dentice M, Luongo C, Elefante A, et al.
Transcription factor Nkx-2.5 induces sodium/iodide symporter gene expression and participates in retinoic acid- and lactation-induced transcription in mammary cells.
Mol Cell Biol. 2004; 24(18):7863-77 [PubMed] Free Access to Full Article Related Publications
The sodium/iodide symporter (NIS) is a plasma membrane protein that mediates active iodide transport in thyroid and mammary cells. It is a prerequisite for radioiodide treatment of thyroid cancer and a promising diagnostic and therapeutic tool for breast cancer. We investigated the molecular mechanisms governing NIS expression in mammary cells. Here we report that Nkx-2.5, a cardiac homeobox transcription factor that is also expressed in the thyroid primordium, is a potent inducer of the NIS promoter. By binding to two specific promoter sites (N2 and W), Nkx-2.5 induced the rNIS promoter (about 50-fold over the basal level). Interestingly, coincident with NIS expression, Nkx-2.5 mRNA and protein were present in lactating, but not virgin, mammary glands in two human breast cancer samples and in all-trans retinoic acid (tRA)-stimulated MCF-7 breast cancer cells. A cotransfected dominant-negative Nkx-2.5 mutant abolished tRA-induced endogenous NIS induction, which shows that Nkx-2.5 activity is critical for this process. Remarkably, in MCF-7 cells, Nkx-2.5 overexpression alone was sufficient to induce NIS and iodide uptake. In conclusion, Nkx-2.5 is a novel relevant transcriptional regulator of mammary NIS and could thus be exploited to manipulate NIS expression in breast cancer treatment strategies.

Nagel S, Kaufmann M, Drexler HG, MacLeod RA
The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2).
Cancer Res. 2003; 63(17):5329-34 [PubMed] Related Publications
A cryptic chromosome rearrangement, t(5;14)(q35.1;q32.2), recently identified in pediatric acute lymphoblastic leukemia (ALL), targets activation of TLX3 at 5q35.1 by juxtaposition with a region downstream of BCL11B at 14q32.2. We describe a novel variant t(5;14) whereby NKX2-5, a related (NK-like family) homeobox gene located approximately 2 Mb telomeric of TLX3, juxtaposes BCL11B in a subset of T-cell ALL cell lines. In this t(5;14) variant, NKX2-5 is expressed instead of TLX3 at both RNA and protein levels. Subsequent expression screening failed to detect involvement of additional NK-like genes in T-cell ALL cells. Our data pinpoint a regulatory region far downstream of BCL11B effecting ectopic homeobox gene activation. This study also identifies in vitro models for both t(5;14) variants and raises questions about diagnostic fluorescence in situ hybridization/reverse transcription-PCR screening in ALL.

Kodama H, Hirotani T, Suzuki Y, et al.
Cardiomyogenic differentiation in cardiac myxoma expressing lineage-specific transcription factors.
Am J Pathol. 2002; 161(2):381-9 [PubMed] Free Access to Full Article Related Publications
We investigated five cases of cardiac myxoma and one case of cardiac undifferentiated sarcoma by light and electron microscopy, in situ hybridization, immunohistochemical staining, and reverse transcriptase-polymerase chain reaction for cardiomyocyte-specific transcription factors, Nkx2.5/Csx, GATA-4, MEF2, and eHAND. Conventional light microscopy revealed that cardiac myxoma and sarcoma cells presented variable cellular arrangements and different histological characteristics. Ultrastructurally, some of the myxoma cells exhibited endothelium-like or immature mesenchymal cell differentiation. Immunohistochemistry for Nkx2.5/Csx, GATA-4, and eHAND was slightly to intensely positive in all myxoma cases. MEF2 immunoreactivity was observed in all cases including the case of sarcoma, thus suggesting myogenic differentiation of myxoma or sarcoma cells. In situ hybridization for Nkx2.5/Csx also revealed that all myxoma cells, but not sarcoma cells, expressed mRNA of the cardiac homeobox gene, Nkx2.5/Csx. Furthermore, nested reverse transcriptase-polymerase chain reaction from formalin-fixed, paraffin-embedded tissue was performed and demonstrated that the Nkx2.5/Csx and eHAND gene product to be detected in all cases, and in three of six cases, respectively. In conclusion, cardiac myxoma cells were found to express various amounts of cardiomyocyte-specific transcription factor gene products at the mRNA and protein levels, thus suggesting cardiomyogenic differentiation. These results support the concept that cardiac myxoma might arise from mesenchymal cardiomyocyte progenitor cells.

Hatcher CJ, Kim MS, Basson CT
Atrial form and function: lessons from human molecular genetics.
Trends Cardiovasc Med. 2000; 10(3):93-101 [PubMed] Related Publications
Molecular genetic analyses of human hereditary disorders that affect cardiac atrial structure and function have recently identified several genes that regulate atrial morphogenesis. Mutations of the TBX5, NKX2.5, EVC, and PRKAR1 alpha genes all result in abnormalities of human atrial growth and development, and mutations in at least one gene results in familial atrial fibrillation and is as yet unidentified. Ongoing studies to find interactions between these transcription factors and intracellular signaling molecules and other as yet unknown genes are establishing critical pathways in human cardiogenesis. Human investigation and experimental animal models of heart development synergize to elucidate etiologies of common congenital heart disease.

Toyota M, Ho C, Ahuja N, et al.
Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification.
Cancer Res. 1999; 59(10):2307-12 [PubMed] Related Publications
CpG island methylation has been linked to tumor suppressor gene inactivation in neoplasia and may serve as a useful marker to clone novel cancer-related genes. We have developed a novel PCR-based method, methylated CpG island amplification (MCA), which is useful for both methylation analysis and cloning differentially methylated genes. Using restriction enzymes that have differential sensitivity to 5-methyl-cytosine, followed by adaptor ligation and PCR amplification, methylated CpG rich sequences can be preferentially amplified. In a model experiment using a probe from exon 1 of the p16 gene, signal was detected from MCA products of a colorectal cancer cell line but not in normal colon mucosa. To identify novel CpG islands differentially methylated in colorectal cancer, we have applied MCA coupled with representational difference analysis to the colon cancer cell line Caco2 as a tester and normal colon mucosa as a driver. Using this strategy, we isolated 33 differentially methylated DNA sequences, including fragments identical to several known genes (PAX6, Versican, alpha-tubulin, CSX, OPT, and rRNA gene). The association of hypermethylation of the clones obtained and transcriptional suppression in colorectal cancer was confirmed by examining the Versican gene, which we found to be silenced in methylated cell lines and reactivated by the methylation inhibitor 5-aza-2'-deoxycytidine. We therefore propose that MCA is a useful technique to study methylation and to isolate CpG islands differentially methylated in cancer.

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