Disease relevance of HOXD3

• Overexpression of the HOX4A (HOXD3) homeobox gene in human erythroleukemia HEL cells results in altered adhesive properties [1].
• Although little or no HOXD3 mRNA was detected in normal brain vessels, increased levels of HOXD3 and its target gene, alpha V beta 3, were found in angiogenic vessels in human brain arteriovenous malformations [2].
• Our previous studies showed that a specific member, HOXD3, when overexpressed, enhanced cell motility and invasiveness of human lung cancer A549 cells (Hamada et al. Int. J. Cancer 2001; 93: 516-25 [19]) [3].
• In the present study, we investigated the roles of HOXD3 in motile and invasive behavior of human malignant melanoma cells [3].

High impact information on HOXD3

• Northern blot analysis showed that integrin beta 3 mRNA levels were significantly increased in the HEL cells overexpressing the HOX4A gene, whereas the integrin beta 1 and alpha IIb mRNA levels did not show a distinct correlation with HOX4A mRNA levels [1].
• In the present study, expression of the HOX4A gene was investigated in human hematopoietic cell lines [1].
• We previously isolated the human homeobox gene HOX4A (HOXD3) on chromosome 2 from a human genomic library and determined its nucleotide sequence [1].
• Furthermore, the sense transfectants overexpressing the HOX4A gene attached more efficiently to fibronectin and collagen than did the antisense transfectants and parental HEL cells [1].
• Fluorescence-activated cell sorting analysis showed that the sense transfectants overexpressing the HOX4A gene expressed increased levels of integrin alpha IIb beta 3 (GP IIb-IIIa) complex as compared with the parental HEL cells and antisense transfectants [1].

Chemical compound and disease context of HOXD3

• Our previous studies showed that a specific member, HOXD3, when overexpressed, upregulates integrin beta3 expression in human erythroleukemia HEL cells and lung cancer A549 cells, and enhances their motility and invasiveness [4].

Biological context of HOXD3

• Finally, HOX4 includes 6 homeoboxes in 70 kb on chromosome 2 [5].
• The HOX4A gene consists of at least two exons separated by a long intron of 1860 bp [6].
• The HOX4A gene, one of the homeobox-containing genes on human chromosome 2, has been isolated by screening a genomic cosmid library with a HOX4B cDNA probe [6].
• A comparison of the predicted HOX4A protein with the HOX2G protein revealed four regions of amino acid sequence similarities: an N-terminal tetrapeptide, a pentapeptide (pre-box) upstream of the homeodomain, the homeodomain and a C-terminal octapeptide [6].
• Interestingly, the HOX4A protein has a sequence, Pro-Ala-Ser-Gln-Ser-Pro-Glu-Arg-Ser, eight amino acids downstream from the homeodomain, which is similar to that containing a phosphorylation site in pp60c-src, Pro-Ala-Ser-Gln-Thr-Pro-Asn-Lys-Thr [6].

Anatomical context of HOXD3

• Of seven melanoma cell lines examined here, six cell lines expressed the HOXD3 gene, whereas normal melanocytes did not [3].
• Compared with parental and control transfectant lines, the HOXD3-overexpressing cell lines showed highly motile and invasive activity [7].
• Reverse transcriptase-mediated polymerase chain reaction analysis showed that the HOX4A gene was expressed in erythroleukemia HEL and K562 cells but not in promyelocytic leukemia HL-60 cells [1].
• Among the genes located at the 5' end of HOX loci RNase protection analysis reveals that one HOX3 gene and four HOX4 genes are weakly expressed in EC stem cells and downregulated upon treatment with 10(-5) M RA [8].
• Gel retardation and Southwestern blot assays showed the presence of a 32-kD homeoprotein with DNA-binding properties typical of a HOX4 homeoprotein in nucleolar extracts of PHA-activated, but not of resting, lymphocytes [9].

Associations of HOXD3 with chemical compounds

• Moreover, expression of HOXD3 led to an increase in the expression of a direct downstream target gene alpha V beta 3 integrin [2].

Regulatory relationships of HOXD3

• HOXD3 enhances motility and invasiveness through the TGF-beta-dependent and -independent pathways in A549 cells [4].

Other interactions of HOXD3

• We have previously shown that transduction of HOXD3, one of homeobox genes, into human lung cancer A549 cells enhances cell motility, invasion and metastasis [10].

Analytical, diagnostic and therapeutic context of HOXD3

• The authors examined HOXD3 expression in human brain vessels by in situ hybridization [2].
• Real-time quantitative RT-PCR assay indicated overexpression of 14 HOX genes in clusters A and B but only 2 genes in clusters C and D. Of the 16 HOX genes, overexpression of paralogs of HOX3, HOX4 and HOX7 is seen in cluster A and B, and of HOX13 in all paralogs [11].

References