Disease relevance of THBS3

• RESULTS: THBS3, SPARC and SPP1 were identified as genes differentially expressed in osteosarcoma [1].
• In particular, THBS3 was expressed at significantly high levels (p = 0.0001) in biopsies from patients with metastasis at diagnosis, which is a predictor of worse overall survival, event-free survival and relapse free survival at diagnosis [1].

High impact information on THBS3

• Although very similar, the signature domains of thrombospondin-1 and -2 differ in several potentially important ways from the domains of thrombospondin-3, -4, and -5 [2].
• This has raised the question of the oligomeric nature of TSP3 and identification of the cysteine residues involved in oligomer formation [3].
• Transient transfections of putative promoter/pCAT constructs document the existence of three promoters, P1 (-127, -49), P2- (-813, -432), and P3 (-1363, -1107), which direct transcription from tsp1, tsp2, and tsp3, respectively [4].
• Metabolic labeling and immunoprecipitation analysis of cells transfected with a TSP3 expression vector revealed it to be an oligomeric heparin binding protein present in both the cell layer and medium [5].
• Finally, a combination of in situ hybridization and immunocytochemistry demonstrated TSP3 to be expressed in a temporal and spatial manner during murine embryogenesis, especially in the gut, cartilage, lung, and central nervous system [5].

Biological context of THBS3

• Analysis of cDNA and genomic sequences showed the THBS3 gene to be composed of 23 exons, 1 more than the number of exons in the previously characterized mouse TSP3 gene [6].
• The THBS3 and mouse TSP3 genes differ in intron sizes, but exon sequences and sizes and positions of insertion of introns are conserved to a high degree [6].
• In the human genome, the TSP-1, TSP-3, TSP-4 and TSP-5 genes lie within paralogous regions that provide insight into the ancestral genomic context of vertebrate TSPs [7].
• Primer extension analyses using 5' upstream primers now identify an additional cluster of tsp between -1035 and -1340 base pairs (tsp3) [4].
• Thus, MTX and THBS3 share a common promoter region and are transcribed convergently, whereas MTX and psGBA are transcribed convergently and have closed apposed polyadenylation sites [8].

Anatomical context of THBS3

• In general, TSP3 mRNA was expressed at high levels in endocrine, muscle, and fetal tissues [9].
• The pattern of expression of TSP3 mRNA was very different: kidney, pituitary gland, trachea, uterus, and fetal kidney had the greatest abundance [9].
• CONCLUSIONS: Keratocyte derived fibroblasts synthesize TSP-2 and TSP-3 when seeded in collagen matrices [10].
• TSP-1 expression is limited to early chondrocytes, in contrast to TSP-3 mRNAs that are found in older proliferative and hypertrophic chondrocytes [11].

Associations of THBS3 with chemical compounds

• Binding assays with 45Ca2+ as ligand and immobilized TSP1, TSP2 and TSP3 demonstrated that all three TSPs are calcium-binding proteins [12].
• In addition to these type III repeats, four type II (EGF-like) repeats and NH2- and COOH-terminal domains are present in thrombospondin 3 [6].

Other interactions of THBS3

• Relative abundance of thrombospondin 2 and thrombospondin 3 mRNAs in human tissues [9].
• Exon A' is located in the TSP3/metaxin intergenic region, 1 kb 5' of exon A [13].
• TSP-3, -4, and COMP were detected only in a minority of cases [14].

Analytical, diagnostic and therapeutic context of THBS3

• THBS3 cDNA clones were obtained by PCR amplification of human fetal lung cDNA using THBS3-specific primers [6].
• After chemotherapy, patients with tumors over-expressing THBS3 have worse relapse free survival [1].
• We demonstrate, using a combination of deletional and site-directed mutagenesis and rotary shadowing electron microscopy, that TSP3, like TSP4 and COMP, is a pentameric molecule [3].
• Phylogenetic analysis using progressive sequence alignment and two parsimony-based algorithms indicates that the COMP gene and a precursor of the thrombospondin-3 and -4 genes were produced by a gene duplication that occurred 750 million years ago [15].

References