Disease relevance of THBS2

• Frequent HOXA11 and THBS2 promoter methylation, and a methylator phenotype in endometrial adenocarcinoma [1].
• However, TSP2, which is also produced by damaged ophthalmic tissue and may be especially important in matrix organisation, seems to augment contraction in anomalous intraocular fibrosis [2].
• Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer [3].
• Thirty-eight of these 61 colon cancers were positive for TSP-2 expression and showed hepatic metastasis at a significantly lower incidence than those without TSP-2 expression (P = 0.02) [3].
• Thrombospondin-2 polymorphism is associated with a reduced risk of premature myocardial infarction [4].

High impact information on THBS2

• A recombinant piece of TSP2 containing this sequence replicated the alpha4beta1 integrin-dependent activities of TSP1 [5].
• The alpha4beta1 integrin recognition site is conserved in TSP2 [5].
• Recombinant pieces of TSP-1 and TSP-2 incorporating combinations of domains that span the entire subunit were produced in insect cells and examined for VWF reductase activity [6].
• Thus, thrombospondin 2 mRNA may be present in the developing brain at low levels in endothelial cells or blood cells [7].
• Thrombospondin 2 mRNA was detected in poly(A) RNA isolated from embryonic spinal cord and cerebellum by polymerase chain reaction, though it was not detected in poly(A) RNA from the avascular retina [7].

Biological context of THBS2

• High rates of HOXA11 and THBS2 methylation were confirmed in the additional nonrecurrent tumors [1].
• High rates of methylation were found in the HOXA11 and THBS2 promoter regions [1].
• The THBS2 gene is located at the distal long arm of chromosome 6 at 6q27 [8].
• These results suggest that tissue-specific differences in expression of the THBS2 gene may be determined, in part, by selection of the transcription start site and resulting differences in the 5' untranslated region [9].
• Comparison of the THBS2 genomic and cDNA sequences revealed that, in contrast to Thbs2, exon 1 is divided into exons 1A and 1B by a small (93 bp) intron [9].

Anatomical context of THBS2

• Expression of TSP-1 and TSP-2 were assessed by reverse transcriptase-polymerase chain reaction in 18 normal endometrium and 55 endometrial cancer samples [10].
• We evaluated whether overexpression of the TSP2 gene show an alteration of various genes by cDNA arrays in the colon carcinoma cell line SW480 [11].
• Thrombospondin 2 mRNA was not detected in the developing central nervous system at any time during development by in situ hybridization [7].
• These data support the notion that tenascin splice variants have distinct roles during development, and that thrombospondin 2 is more likely to be playing a role associated with the morphogenesis of connective tissue than neuronal development [7].
• TSP-2 mRNA expression in normal cervix was significantly higher than that in cases involving cervical cancer (P = 0.032) [12].

Associations of THBS2 with chemical compounds

• The THBS2 signature domain is stabilized by these interactions and by a network of 30 bound Ca(2+) ions and 18 disulfide bonds [13].
• Here, we describe the 2.6-A-resolution crystal structure of the glycosylated signature domain of human THBS2, which includes three epidermal growth factor-like modules, 13 aspartate-rich repeats and a lectin-like module [13].
• Alkylation of Cys974 in the C-terminal TSP-1 construct, which is a serine in TSP-2, ablated VWF reductase activity [6].
• Atomic absorption spectroscopy demonstrated that the thrombospondin-4 constructs bind seven less calcium than the thrombospondin-2 construct at 0.6 mM CaCl2 [14].
• Thrombospondin 2 (TSP2) is an extracellular matrix glycoprotein involved in tumor progression and angiogenesis [11].

Regulatory relationships of THBS2

• An N-terminal 80 kDa recombinant fragment of human thrombospondin-2 inhibits vascular endothelial growth factor induced endothelial cell migration in vitro and tumor growth and angiogenesis in vivo [15].
• In cervical cancer, TSP-2 appears only to be highly co-expressed with MMP-2 (P<0.0001) [16].

Other interactions of THBS2

• Thrombospondin 1, thrombospondin 2 and the eye [2].
• None of the 24 case-matched bloods had HOXA11 methylation, whereas three blood DNAs showed THBS2 methylation [1].
• These results suggest that colon cancer metastasis is critically determined by angiogenesis resulting from the balance between the angioinhibitory factor TSP-2 and angiogenic factor VEGF-189 [3].
• The THBS2 and THBS4 associations have since been replicated [17].
• Protein production of MMP2 and MMP9 decreased in the transformants overexpressing the TSP2 gene [11].

Analytical, diagnostic and therapeutic context of THBS2

• We examined TSP-1 and TSP-2 gene expression by reverse transcription polymerase chain reaction (RT-PCR) analysis in 61 colon cancers [3].
• In 2 mM CaCl2, the near UV circular dichroism spectra of thrombospondin-2, but not thrombospondin-4, contain a positive band at 292 nm that disappears upon calcium chelation [14].
• Titrations of the spectra demonstrated lower cooperativity and affinity for binding of calcium to thrombospondin-4 compared with thrombospondin-2 [14].
• Expression of TSP1 and TSP2 was determined by immunohistochemistry and SDS-polyacrylamide gel electrophoresis at 0, 2, 4, 6, 8, 24, 48, and 72 h after infection (ai) [18].
• TSP-2 in particular provided protection in excess of the 40% benchmark set by the World Health Organization for progression of schistosome vaccine antigens into clinical trials [19].

References