Disease relevance of Thbs1

• Fra1 Tg mice, as well as Thbs1(-/-) Thbs2(-/-) mice, which do not show osteosclerosis, exhibit an edge-to-edge bite phenotype associated with craniofacial dysmorphism [1].
• Angiogenic response caused by oncolytic herpes simplex virus-induced reduced thrombospondin expression can be prevented by specific viral mutations or by administering a thrombospondin-derived peptide [2].
• The matricellular angiogenesis inhibitor, thrombospondin (TSP) 2, has been shown to be an important modulator of wound healing and the foreign body response [3].
• Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model [4].
• CONCLUSIONS: Corneal avascularity during development is redundantly regulated, shown by the fact that lack of the antiangiogenic factors TSP-1 and/or -2 resulted in no spontaneous corneal angiogenesis [5].

High impact information on Thbs1

• These findings establish a crucial role of an Akt-thrombospondin axis in angiogenesis [6].
• These effects are mediated by an upregulation of the antiangiogenic factor thrombospondin-1, independently of classical arachidonic acid metabolism [7].
• Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface [8].
• Here we show that two such inhibitors, thrombospondin-1 and pigment epithelium-derived factor, derive specificity for remodeling vessels from their dependence on Fas/Fas ligand (FasL)-mediated apoptosis to block angiogenesis [9].
• Properdin, the terminal complement components, thrombospondin and the circumsporozoite protein of malaria parasites contain similar sequence motifs [10].

Chemical compound and disease context of Thbs1

• Using a tet-repressible expression system, we demonstrate that murine TSP1 delayed the onset of tumor growth when produced in the tumor bed by rat fibrosarcoma tumor cells or by stromal fibroblasts coinjected with unmodified C6 glioma tumor cells [11].
• A baculovirus system was used to express full-length recombinant mouse thrombospondin 2 (rTSP2) as a disulfide-bonded homotrimer with an NH2 terminus beginning with Asp20.rTSP2, like TSP1, was more sensitive to trypsin digestion if depleted of calcium ion [12].
• Interferon-{beta} inhibits bleomycin-induced lung fibrosis by decreasing transforming growth factor-{beta} and thrombospondin [13].
• All animals had metastases at 6 months, while metastasis did not develop following the combination of carboplatin with TSP-1 or endostatin [14].
• Interestingly, this effect was relatively ras-specific, as doxycycline did not alter TSP-1 expression in several cell lines (e.g., 528neu2 fibrosarcoma, B16F1 melanoma, and Lewis lung carcinoma) harbouring other types of transforming alterations [15].

Biological context of Thbs1

• Thbs2 is located on chromosome 17, band A3, whereas Thbs1 was found on chromosome 2, band F [16].
• The exon/intron organization of Thbs2 is highly conserved in comparison with Thbs1 in that exon size and the pattern of interruption of the reading frame by introns are preserved, but there is a marked divergence in coding sequence, primarily in the first 7 exons [16].
• The cell adhesion regulating extracellular matrix glycoprotein, thrombospondin (TSP), causes a loss of focal adhesion plaques from spread endothelial cells and fibroblasts [17].
• Our data demonstrate that the consequences of a lack of TSP1 predominate in the response of double-null mice, and dictate the course of wound healing [18].
• In this report, the primary structures of human TSP, mouse TSP1 (mTSP1), mouse TSP2 (mTSP2), and chicken TSP are compared; and the expression of mTSP1 and mTSP2 during embryogenesis and growth factor-mediated cell proliferation is examined [19].

Anatomical context of Thbs1

• In marked contrast to Thbs1, the Thbs2 gene is not induced by serum in NIH 3T3 cells; promoter sequences in the two genes are also very different [16].
• We found that expression of Thbs1 and Thbs2 was reduced in Fra1 Tg osteoblasts [1].
• Re-expression of TSP-1 and TSP-2 in mice transplanted with wild-type bone marrow corrected the angiogenic abnormalities in Akt1(-/-) mice [6].
• Swiss 3T3 fibroblasts express both TSP1 and TSP2, and, therefore, an important question is whether TSP in such cells is expressed as homotrimers or as heterotrimers [20].
• Immunohistochemical analysis showed that, similar to TSP1-null mice, the granulation tissue of double-null mice was not excessively vascularized [18].

Associations of Thbs1 with chemical compounds

• Thrombospondin (TSP) is an extracellular matrix glycoprotein whose expression has been associated with a variety of cellular processes including growth and embryogenesis [19].
• Peptides from putative heparin binding sequences of the amino-terminal heparin-binding domain of TSP were synthesized and tested for their ability to cause loss of focal adhesions [17].
• Both proteins contain NH2-terminal, COOH-terminal, and procollagen homology domains, and type I (TSP or properdin), type II (EGF-like), and type III (Ca(2+)-binding) repeats [21].
• The presence of various consensus sequences suggests that thrombospondin gene expression is regulated by cAMP, cytokines, and steroid hormones [22].
• The TSP-1-null and beta6-null mice exhibited a five to eight-fold increase in granulocyte recruitment to the lung three days after exposure to lipopolysaccharide [23].
• Thrombospondin-1 also inhibits cGMP-mediated activation of cGMP-dependent protein kinase and thereby prevents phosphorylation of VASP [24].

Physical interactions of Thbs1

• These studies provide a molecular basis for both latency and activation by TSP1 through the LSKL sequence of LAP binding to the RKPK sequence of mature TGF-beta [25].

Regulatory relationships of Thbs1

• Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1 [26].
• Thrombospondin 1 (TSP1) is a multifunctional protein able to activate TGFbeta and to inhibit angiogenesis in vivo [11].
• These results indicate that TSP-1 regulates the multimeric size and therefore hemostatic activity of vWF [27].
• They also identify 2 independent pathways by which TSP-1 can block FGF-2 and VEGF angiogenic signals on endothelial cells [28].
• Immunocytochemical staining identified the injured proximal tubules as the predominant sites of expression of TSP-1 in IR injury and showed colocalization of TSP-1 with activated caspase-3 [29].

Other interactions of Thbs1

• PURPOSE: The role of thrombospondin (TSP)-1 in TGF-beta activation and T-cell suppression was studied in the retinal pigment epithelial (RPE) cells, a monolayer of pigmented cells that line the subretinal space, an immune-privileged site in the eye [30].
• The effects of TSP-1 on adenoma formation and development into cancerous lesions has been evaluated in the Min(/+) (multiple intestinal neoplasia) mouse model [4].
• Thus, our results demonstrate that in the absence of TSP1, the proangiogenic signaling is enhanced, possibly through up-regulation of fibronectin expression [31].
• TSP1 is a trimeric cell surface and extracellular matrix molecule [20].
• Furthermore as in TSP1-nulls, decreases in macrophage recruitment and in the levels of monocyte chemoattractant protein-1 indicated that the inflammatory phase of the wound-healing response was impaired in double-null mice [18].

Analytical, diagnostic and therapeutic context of Thbs1

• Corneas and irides of TSP-1(-/-), TSP-2(-/-), and TSP-1,2(-/-) mice aged 2, 3, and 6 months, and wild-type control mice, were analyzed for spontaneous angiogenesis biomicroscopically, histologically, and with CD31 immunohistochemistry [5].
• METHODS: Expression of TSP-1 and -2 mRNA and protein was assayed in cornea and iris stroma by RT-PCR and Western blot [5].
• To study the functions of these proteins, we have used in situ hybridization and RNAse protection assays to compare the expression of the genes encoding thrombospondin 1, 2, and 3 during murine embryogenesis [32].
• These results suggest that TSP-1 gene therapy may have therapeutic potential for the management of rheumatoid arthritis [33].
• Thrombospondin 1 as an effective gene therapeutic strategy in collagen-induced arthritis [33].

References