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DLX4 (distal-less homeobox 4)

Written2011-01Patricia E Berg, Saurabh Kirolikar
The George Washington University Medical Center, Washington DC 20037, USA (PEB); The George Washington University, Department of Biochemistry, Molecular Biology, Washington DC 20037, USA (SK)

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Identity

Alias_namesDLX7
DLX9
Alias_symbol (synonym)DLX8
BP1
Other alias
HGNC (Hugo) DLX4
LocusID (NCBI) 1748
Atlas_Id 49827
Location 17q21.33  [Link to chromosome band 17q21]
Location_base_pair Starts at 48050130 and ends at 48052323 bp from pter ( according to hg19-Feb_2009)  [Mapping DLX4.png]

DNA/RNA

Note BP1, DLX4 and DLX7 are not interchangeable names for the same gene, as sometimes claimed. We cloned a cDNA encoding BP1 from a library made from K562 erythroleukemia cells, often used as a model for hemoglobin switching. After it was sequenced it was apparent that part of the BP1 sequence was identical to that of two other published "genes", DLX4 and DLX7; upstream of nucleotide 565 of BP1, all three had entirely different sequences, while downstream of that site the sequences were identical (Fu et al., 2001; Chase et al., 2002). This suggested that the three might be isoforms of one gene, differing only in the first exon; this can occur by alternative splicing or by use of alternative promoters. DLX7 had been mapped to 17q21-22 (Nakamura et al., 1996). We then mapped BP1, which also mapped to the same chromosomal region (Fu et al., 2001). In fact, our BAC included sequences from both BP1 and DLX7. When we published the paper showing that BP1 is a repressor of the beta-globin gene and identifying BP1, DLX4 and DLX7 as isoforms, to prevent confusion in the literature we gave the gene a single name, DLX4, based on the fact that the DLX4 DNA sequence was published first (Chase et al., 2002). Thus, the DLX4 gene encodes at least three different proteins with presumably different functions, DLX4, BP1 and DLX7. The NCBI Database is somewhat confusing in this regard - the gene is called DLX4, but BP1 is named DLX4 variant 1 and DLX7 is called DLX4 variant 2.
 
  The red lines indicate the predicted ORFs. Number 565 indicates the nucleotide of BP1 where divergence occurs among BP1, DLX4, and DLX7. HB is the homeobox region. The regions between the two vertical lines indicate the regions of DNA identity. The complete ORF is not available for DLX4.
Description The DLX4 gene is located at 17q21.33 and is about 5761 bp in length (chr17:48,046,562-48,052,322).
Transcription Three different mRNAs are expressed by DLX4, BP1 and DLX7. BP1 mRNA is about 2012 bp.

Protein

 
  Amino acid sequence alignment between BP1 (Q92988-1), DLX7 (Q92988-2) and an unidentified isoform of DLX4 (Q92988-3). The sequences were obtained from the UniProt database which has incorrectly identified the BP1 sequence as DLX4.
Description The BP1 protein is an alternatively spliced isoform derived from the DLX4 gene. The protein is about 240 aa in length with the calculated molecular weight of 26 kDa. The observed weight of the protein is about 36 kDa on Western blots using lysates from breast cancer and prostate cancer cell lines. This difference may be due to post-translational modifications of BP1 protein. BP1 protein has a 116 aa N-terminal region, 60 aa homeobox domain and a 64 aa C-terminal domain, while DLX7 is 168 aa.
Expression In normal tissue: BP1 protein is expressed in adult kidney and placenta and in low levels in normal breast and fetal liver (Chase et al., 2002).
Localisation Both nuclear and cytoplasmic immunostaining are seen in BP1 positive breast tumors and prostate tumors (Man et al., 2005; Schwartz et al., 2009).
Function Functionally, we demonstrated that BP1 is a repressor of the beta-globin gene, while DLX7 binds to the same DNA sequence upstream of the beta-globin gene but lacks the ability to repress it (Fu et al., 2001; Chase et al., 2002). Thus, the functions of BP1 and DLX7 are clearly different in this context. BP1 acts to repress embryonic and fetal globin genes during early development but is itself repressed during normal adult erythropoiesis.
BP1 overexpression induces increased Bcl-2 expression and decreased apoptosis. pBP1 binds to the regulatory region of the bcl-2 gene, an anti-apoptotic gene, resulting in elevated expression of Bcl-2 protein and resistance to TNF-alpha in MCF-7 breast cancer cells (Stevenson et al., 2007). Increased BP1 is associated with decreased cleavage of caspase-7, caspase-8 and caspase-9, and increased expression of PARP. Thus, high BP1 expression can lead to decreased cell death and, as shown below, increased proliferation.
BP1 appears to be a repressor of BRCA1. Three breast cancer cell lines engineered to overexpress BP1 show decreased BRCA1 RNA and protein, while cells in which BP1 is knocked down by siRNA treatment show increased BRCA1 expression, suggesting that BP1 activity may contribute to reduced BRCA1 in some breast cancers (Kluk et al., 2010).

Implicated in

Note
  
Entity Breast cancer
Note BP1 is activated in about 80% of invasive ductal breast (IDC) tumors. Aberrant expression of BP1 was shown by semi-quantitative RT-PCR, where 80% of tumors were BP1 positive, and by immunostaining, where 81% of tumors were BP1 positive, a remarkable agreement between mRNA and protein expression (Fu et al., 2003; Man et al., 2005). Surprisingly, 89% of the tumors of African American women (AAW) were BP1 positive, compared with 57% of the tumors of Caucasian women (p=0.04). In addition, 100% of ER negative tumors were BP1 positive, compared with 73% of ER positive (p=0.03). Both tumors of AAW and ER negative tumors are associated with aggressiveness. A group in China quantitated BP1 mRNA in the tumors of 142 Chinese women, discovering that 65% of their tumors were BP1 positive, and confirming an association between high BP1 mRNA expression and ER negative tumors (Yu et al., 2008b). Inflammatory breast cancer (IBC) is an extremely aggressive breast cancer, with approximately half the survival seen in IDC; 100% of the forty-six cases of IBC we examined were highly BP1 immunoreactive, suggesting an association between aggressiveness, frequency of BP1 positivity, and BP1 protein (pBP1) staining intensity (Man et al., 2009).
pBP1 expression correlates with breast cancer progression. The frequency of pBP1 positivity, distribution and intensity of BP1 expression all increased with the progression of tumor development from 0% (normal) to 21% in hyperplasia, 46% in ductal carcinoma in situ, and 81% in IDC (p<0.0001) (Man et al., 2005). This suggests BP1 expression may be an important upstream factor in an oncogenic pathway and may contribute to tumor progression.
Expression of BP1 is associated with larger tumor size. We have recently shown a correlation between BP1 mRNA or protein expression and tumor size in women with invasive ductal breast cancer. This correlation is also true in a mouse model (submitted).
BP1 positivity correlates with increased proliferation. BP1 positive cells were significantly more frequently positive for Ki67, a proliferation marker, when 5000 BP1 positive tumor cells were compared with 5000 BP1 negative tumor cells (Man et al., 2005).
BP1 appears to be associated with metastasis. Among the IBC cases, nine had metastasized. The lymph nodes corresponding to these cases were all BP1 positive, providing evidence that BP1 is expressed in metastasis (Man et al., 2009). Moreover, BP1 positive cells were observed in lymphatic ducts of patients with metastatic IBC. A correlation between high BP1 mRNA levels and metastasis in invasive ductal breast cancer was observed by Yu et al. (2008b).
BP1 mRNA levels are associated with survival. Kaplan-Meier curves revealed that patients with grade III tumors expressing high BP1 mRNA levels showed decreased survival compared with patients whose grade III tumors contained lower BP1 mRNA levels (Yu et al., 2008b).
BP1 is activated by DNA amplification. It is important to determine the factors that activate BP1. Approximately 33% of the tumors we examined from women with metastatic breast cancer exhibited DNA amplification of BP1. Amplification was associated with BP1 positivity by immunostaining in all cases (Cavalli et al., 2008).

Overall, the data strongly suggest that BP1 may be a useful new biomarker in early detection of breast cancer and a potential therapeutic target.

  
  
Entity Leukemia
Note We examined BP1 in the bone marrow of leukemia patients by semi-quantitative RT-PCR, finding that BP1 was activated in 63% of acute myeloid leukemias (AML), including 81% of pediatric and 47% of adult patients with AML, in 32% of T-cell acute lymphocytic leukemias (ALL) but not in the pre-B ALL cases (Haga et al., 2000). Expression of BP1 occurred in primitive leukemia cells and in CD34 positive progenitors. In the same study we examined expression of DLX4 and DLX7 by designing primers specific for each isoform. Interestingly, the three isoforms were frequently co-expressed in the same cases. Next we compared the growth-inhibitory and cyto-differentiating activities of all-trans retinoic acid (ATRA) in two acute promyelocytic leukemia (APL) cells lines, NB4 (ATRA-responsive) and R4 (ATRA-resistant) cells relative to BP1 levels (Awwad et al., 2008). NB4 cells and R4 cells both expressed BP1; BP1 was repressed after ATRA treatment of NB4 cells but not R4 cells. In NB4 cells engineered to overexpress BP1, proliferation was no longer inhibited and differentiation was reduced two- to three-fold. In patients, BP1 levels were increased in all pre-treatment APL patients tested, while BP1 expression was decreased in 91% of patients after combined ATRA and chemotherapy treatment. Two patients underwent disease relapse during follow up; one patient exhibited a 42-fold increase in BP1 expression, while the other showed no change. This suggests BP1 may be part of a pathway involved in resistance to therapy.
  
  
Entity Prostate cancer
Note Prostate cancer, another hormone dependent solid tumor, was examined for activation of BP1 (Schwartz et al., 2008). Significant BP1 immunoreactivity was identified in 70% of prostatic tumors, whether the analysis was performed on tissue sections (50 cases) or tissue microarray platforms (123 cases). We also observed low BP1 immunostaining in 42% of hyperplastic cells, similar to the 46% BP1 positivity in hyperplastic breast cells. Compared to normal and hyperplastic tissues, the malignant tissues consistently showed the highest number of BP1 positive cells and the highest intensity of BP1 immunostaining, similar to our observations in breast. In tissue sections, twelve cases with paired carcinoma and prostatic intraepithelial neoplasia (PIN) showed agreement, both components exhibiting strong immunoreactivity. Tumor proliferation, assayed with Ki67 immunostaining, was higher in cancer cells that were BP1 positive relative to those that were BP1 negative, in agreement with the data in breast cancer cells. These findings suggest that BP1 is an important upstream factor in the carcinogenic pathway of prostate cancer and that the expression of BP1 may reflect or directly contribute to tumor progression and/or invasion.
  
  
Entity Non-small cell lung cancer (NSCLC)
Note An interesting study by Yu et al. (2008a) demonstrated that high BP1 mRNA levels occur in NSCLC tumors, compared with adjacent normal cells or normal lung samples. High mRNA levels are associated with stage III tumors, lower disease free survival (DFS) and lower overall survival. In fact, high BP1 mRNA is an independent predictor of DFS.
  

Bibliography

Overexpression of BP1, a homeobox gene, is associated with resistance to all-trans retinoic acid in acute promyelocytic leukemia cells.
Awwad RT, Do K, Stevenson H, Fu SW, Lo-Coco F, Costello M, Campbell CL, Berg PE.
Ann Hematol. 2008 Mar;87(3):195-203. Epub 2007 Nov 20.
PMID 18026954
 
Amplification of the BP1 homeobox gene in breast cancer.
Cavalli LR, Man YG, Schwartz AM, Rone JD, Zhang Y, Urban CA, Lima RS, Haddad BR, Berg PE.
Cancer Genet Cytogenet. 2008 Nov;187(1):19-24.
PMID 18992636
 
BP1, a homeodomain-containing isoform of DLX4, represses the beta-globin gene.
Chase MB, Fu S, Haga SB, Davenport G, Stevenson H, Do K, Morgan D, Mah AL, Berg PE.
Mol Cell Biol. 2002 Apr;22(8):2505-14.
PMID 11909945
 
Distinct functions of two isoforms of a homeobox gene, BP1 and DLX7, in the regulation of the beta-globin gene.
Fu S, Stevenson H, Strovel JW, Haga SB, Stamberg J, Do K, Berg PE.
Gene. 2001 Oct 31;278(1-2):131-9.
PMID 11707330
 
Correlation of expression of BP1, a homeobox gene, with estrogen receptor status in breast cancer.
Fu SW, Schwartz A, Stevenson H, Pinzone JJ, Davenport GJ, Orenstein JM, Gutierrez P, Simmens SJ, Abraham J, Poola I, Stephan DA, Berg PE.
Breast Cancer Res. 2003;5(4):R82-7. Epub 2003 Apr 22.
PMID 12817998
 
BP1, a new homeobox gene, is frequently expressed in acute leukemias.
Haga SB, Fu S, Karp JE, Ross DD, Williams DM, Hankins WD, Behm F, Ruscetti FW, Chang M, Smith BD, Becton D, Raimondi SC, Berg PE.
Leukemia. 2000 Nov;14(11):1867-75.
PMID 11069021
 
BP1, an isoform of DLX4 homeoprotein, negatively regulates BRCA1 in sporadic breast cancer.
Kluk BJ, Fu Y, Formolo TA, Zhang L, Hindle AK, Man YG, Siegel RS, Berg PE, Deng C, McCaffrey TA, Fu SW.
Int J Biol Sci. 2010 Sep 10;6(5):513-24.
PMID 20877436
 
Expression of BP1, a novel homeobox gene, correlates with breast cancer progression and invasion.
Man YG, Fu SW, Schwartz A, Pinzone JJ, Simmens SJ, Berg PE.
Breast Cancer Res Treat. 2005 Apr;90(3):241-7.
PMID 15830137
 
BP1, a putative signature marker for inflammatory breast cancer and tumor aggressiveness.
Man YG, Schwartz A, Levine PH, Teal C, Berg PE.
Cancer Biomark. 2009;5(1):9-17.
PMID 19242057
 
Genomic analysis of a new mammalian distal-less gene: Dlx7.
Nakamura S, Stock DW, Wydner KL, Bollekens JA, Takeshita K, Nagai BM, Chiba S, Kitamura T, Freeland TM, Zhao Z, Minowada J, Lawrence JB, Weiss KM, Ruddle FH.
Genomics. 1996 Dec 15;38(3):314-24.
PMID 8975708
 
BP1, a homeoprotein, is significantly expressed in prostate adenocarcinoma and is concordant with prostatic intraepithelial neoplasia.
Schwartz AM, Man YG, Rezaei MK, Simmens SJ, Berg PE.
Mod Pathol. 2009 Jan;22(1):1-6. Epub 2008 Oct 17.
PMID 18931648
 
BP1 transcriptionally activates bcl-2 and inhibits TNFalpha-induced cell death in MCF7 breast cancer cells.
Stevenson HS, Fu SW, Pinzone JJ, Rheey J, Simmens SJ, Berg PE.
Breast Cancer Res. 2007;9(5):R60.
PMID 17854498
 
Prognostic significance of BP1 mRNA expression level in patients with non-small cell lung cancer.
Yu M, Wan Y, Zou Q.
Clin Biochem. 2008a Jul;41(10-11):824-30. Epub 2008 Apr 4.
PMID 18420035
 
Expression level of beta protein 1 mRNA in Chinese breast cancer patients: a potential molecular marker for poor prognosis.
Yu M, Yang Y, Shi Y, Wang D, Wei X, Zhang N, Niu R.
Cancer Sci. 2008b Jan;99(1):173-8. Epub 2007 Nov 12.
PMID 17999690
 

Citation

This paper should be referenced as such :
Berg, PE ; Kirolikar, S
DLX4 (distal-less homeobox 4)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(8):658-661.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/DLX4ID49827ch17q21.html


External links

Nomenclature
HGNC (Hugo)DLX4   2917
Cards
AtlasDLX4ID49827ch17q21
Entrez_Gene (NCBI)DLX4  1748  distal-less homeobox 4
AliasesBP1; DLX7; DLX8; DLX9; 
OFC15
GeneCards (Weizmann)DLX4
Ensembl hg19 (Hinxton)ENSG00000108813 [Gene_View]  chr17:48050130-48052323 [Contig_View]  DLX4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000108813 [Gene_View]  chr17:48050130-48052323 [Contig_View]  DLX4 [Vega]
ICGC DataPortalENSG00000108813
TCGA cBioPortalDLX4
AceView (NCBI)DLX4
Genatlas (Paris)DLX4
WikiGenes1748
SOURCE (Princeton)DLX4
Genetics Home Reference (NIH)DLX4
Genomic and cartography
GoldenPath hg19 (UCSC)DLX4  -     chr17:48050130-48052323 +  17q21.33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)DLX4  -     17q21.33   [Description]    (hg38-Dec_2013)
EnsemblDLX4 - 17q21.33 [CytoView hg19]  DLX4 - 17q21.33 [CytoView hg38]
Mapping of homologs : NCBIDLX4 [Mapview hg19]  DLX4 [Mapview hg38]
OMIM601911   
Gene and transcription
Genbank (Entrez)AF254115 BC005812 BC014419 BC016145 BG479840
RefSeq transcript (Entrez)NM_001934 NM_138281
RefSeq genomic (Entrez)NC_000017 NC_018928 NG_030592 NT_010783 NW_004929407
Consensus coding sequences : CCDS (NCBI)DLX4
Cluster EST : UnigeneHs.591167 [ NCBI ]
CGAP (NCI)Hs.591167
Alternative Splicing GalleryENSG00000108813
Gene ExpressionDLX4 [ NCBI-GEO ]   DLX4 [ EBI - ARRAY_EXPRESS ]   DLX4 [ SEEK ]   DLX4 [ MEM ]
Gene Expression Viewer (FireBrowse)DLX4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1748
GTEX Portal (Tissue expression)DLX4
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92988   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92988  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92988
Splice isoforms : SwissVarQ92988
PhosPhoSitePlusQ92988
Domaine pattern : Prosite (Expaxy)HOMEOBOX_1 (PS00027)    HOMEOBOX_2 (PS50071)   
Domains : Interpro (EBI)Homeobox_CS    Homeobox_dom    Homeobox_metazoa    Homeodomain-like    HTH_motif   
Domain families : Pfam (Sanger)Homeobox (PF00046)   
Domain families : Pfam (NCBI)pfam00046   
Domain families : Smart (EMBL)HOX (SM00389)  
Conserved Domain (NCBI)DLX4
DMDM Disease mutations1748
Blocks (Seattle)DLX4
SuperfamilyQ92988
Human Protein AtlasENSG00000108813
Peptide AtlasQ92988
HPRD03553
IPIIPI00024380   IPI00219408   IPI00449036   
Protein Interaction databases
DIP (DOE-UCLA)Q92988
IntAct (EBI)Q92988
FunCoupENSG00000108813
BioGRIDDLX4
STRING (EMBL)DLX4
ZODIACDLX4
Ontologies - Pathways
QuickGOQ92988
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  regulation of transcription, DNA-templated  multicellular organism development  sequence-specific DNA binding  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding  transcriptional repressor activity, RNA polymerase II core promoter proximal region sequence-specific binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  regulation of transcription, DNA-templated  multicellular organism development  sequence-specific DNA binding  
NDEx NetworkDLX4
Atlas of Cancer Signalling NetworkDLX4
Wikipedia pathwaysDLX4
Orthology - Evolution
OrthoDB1748
GeneTree (enSembl)ENSG00000108813
Phylogenetic Trees/Animal Genes : TreeFamDLX4
HOVERGENQ92988
HOGENOMQ92988
Homologs : HomoloGeneDLX4
Homology/Alignments : Family Browser (UCSC)DLX4
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerDLX4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)DLX4
dbVarDLX4
ClinVarDLX4
1000_GenomesDLX4 
Exome Variant ServerDLX4
ExAC (Exome Aggregation Consortium)DLX4 (select the gene name)
Genetic variants : HAPMAP1748
Genomic Variants (DGV)DLX4 [DGVbeta]
DECIPHER (Syndromes)17:48050130-48052323  ENSG00000108813
CONAN: Copy Number AnalysisDLX4 
Mutations
ICGC Data PortalDLX4 
TCGA Data PortalDLX4 
Broad Tumor PortalDLX4
OASIS PortalDLX4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICDLX4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDDLX4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch DLX4
DgiDB (Drug Gene Interaction Database)DLX4
DoCM (Curated mutations)DLX4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)DLX4 (select a term)
intoGenDLX4
NCG5 (London)DLX4
Cancer3DDLX4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601911   
Orphanet
MedgenDLX4
Genetic Testing Registry DLX4
NextProtQ92988 [Medical]
TSGene1748
GENETestsDLX4
Huge Navigator DLX4 [HugePedia]
snp3D : Map Gene to Disease1748
BioCentury BCIQDLX4
ClinGenDLX4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1748
Chemical/Pharm GKB GenePA27372
Clinical trialDLX4
Miscellaneous
canSAR (ICR)DLX4 (select the gene name)
Probes
Litterature
PubMed42 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineDLX4
EVEXDLX4
GoPubMedDLX4
iHOPDLX4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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