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Gene Review

Thbs1  -  thrombospondin 1

Mus musculus

Synonyms: TSP-1, TSP1, Thbs-1, Thrombospondin-1, Tsp1, ...
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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


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


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


  1. Reduced expression of thrombospondins and craniofacial dysmorphism in mice overexpressing fra1. Nishiwaki, T., Yamaguchi, T., Zhao, C., Amano, H., Kurt, D.H., Bornstein, P., Toyama, Y., Matsuo, K. J. Bone Miner. Res. (2006) [Pubmed]
  2. 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. Aghi, M., Rabkin, S.D., Martuza, R.L. Cancer Res. (2007) [Pubmed]
  3. Altered extracellular matrix remodeling and angiogenesis in sponge granulomas of thrombospondin 2-null mice. Kyriakides, T.R., Zhu, Y.H., Yang, Z., Huynh, G., Bornstein, P. Am. J. Pathol. (2001) [Pubmed]
  4. Thrombospondin 1--a regulator of adenoma growth and carcinoma progression in the APC(Min/+) mouse model. Gutierrez, L.S., Suckow, M., Lawler, J., Ploplis, V.A., Castellino, F.J. Carcinogenesis (2003) [Pubmed]
  5. Roles of thrombospondin-1 and -2 in regulating corneal and iris angiogenesis. Cursiefen, C., Masli, S., Ng, T.F., Dana, M.R., Bornstein, P., Lawler, J., Streilein, J.W. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  6. Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Chen, J., Somanath, P.R., Razorenova, O., Chen, W.S., Hay, N., Bornstein, P., Byzova, T.V. Nat. Med. (2005) [Pubmed]
  7. Trans-arachidonic acids generated during nitrative stress induce a thrombospondin-1-dependent microvascular degeneration. Kermorvant-Duchemin, E., Sennlaub, F., Sirinyan, M., Brault, S., Andelfinger, G., Kooli, A., Germain, S., Ong, H., d'Orleans-Juste, P., Gobeil, F., Zhu, T., Boisvert, C., Hardy, P., Jain, K., Falck, J.R., Balazy, M., Chemtob, S. Nat. Med. (2005) [Pubmed]
  8. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Silvie, O., Rubinstein, E., Franetich, J.F., Prenant, M., Belnoue, E., Rénia, L., Hannoun, L., Eling, W., Levy, S., Boucheix, C., Mazier, D. Nat. Med. (2003) [Pubmed]
  9. Inducer-stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium-derived factor. Volpert, O.V., Zaichuk, T., Zhou, W., Reiher, F., Ferguson, T.A., Stuart, P.M., Amin, M., Bouck, N.P. Nat. Med. (2002) [Pubmed]
  10. Properdin, the terminal complement components, thrombospondin and the circumsporozoite protein of malaria parasites contain similar sequence motifs. Goundis, D., Reid, K.B. Nature (1988) [Pubmed]
  11. In vivo mechanisms by which tumors producing thrombospondin 1 bypass its inhibitory effects. Filleur, S., Volpert, O.V., Degeorges, A., Voland, C., Reiher, F., Clézardin, P., Bouck, N., Cabon, F. Genes Dev. (2001) [Pubmed]
  12. Properties of recombinant mouse thrombospondin 2 expressed in Spodoptera cells. Chen, H., Sottile, J., O'Rourke, K.M., Dixit, V.M., Mosher, D.F. J. Biol. Chem. (1994) [Pubmed]
  13. Interferon-{beta} inhibits bleomycin-induced lung fibrosis by decreasing transforming growth factor-{beta} and thrombospondin. Azuma, A., Li, Y.J., Abe, S., Usuki, J., Matsuda, K., Henmi, S., Miyauchi, Y., Ueda, K., Izawa, A., Sone, S., Hashimoto, S., Kudoh, S. Am. J. Respir. Cell Mol. Biol. (2005) [Pubmed]
  14. Low dose carboplatin combined with angiostatic agents prevents metastasis in human testicular germ cell tumor xenografts. Abraham, D., Abri, S., Hofmann, M., Höltl, W., Aharinejad, S. J. Urol. (2003) [Pubmed]
  15. Restoration of thrombospondin 1 expression in tumor cells harbouring mutant ras oncogene by treatment with low doses of doxycycline. Kalas, W., Gilpin, S., Yu, J.L., May, L., Krchnakova, H., Bornstein, P., Rak, J. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  16. A second thrombospondin gene in the mouse is similar in organization to thrombospondin 1 but does not respond to serum. Bornstein, P., Devarayalu, S., Li, P., Disteche, C.M., Framson, P. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  17. Heparin-binding peptides from thrombospondins 1 and 2 contain focal adhesion-labilizing activity. Murphy-Ullrich, J.E., Gurusiddappa, S., Frazier, W.A., Höök, M. J. Biol. Chem. (1993) [Pubmed]
  18. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Agah, A., Kyriakides, T.R., Lawler, J., Bornstein, P. Am. J. Pathol. (2002) [Pubmed]
  19. Characterization of mouse thrombospondin 2 sequence and expression during cell growth and development. Laherty, C.D., O'Rourke, K., Wolf, F.W., Katz, R., Seldin, M.F., Dixit, V.M. J. Biol. Chem. (1992) [Pubmed]
  20. Thrombospondin 1 and thrombospondin 2 are expressed as both homo- and heterotrimers. O'Rourke, K.M., Laherty, C.D., Dixit, V.M. J. Biol. Chem. (1992) [Pubmed]
  21. Thrombospondins: structure and regulation of expression. Bornstein, P. FASEB J. (1992) [Pubmed]
  22. Characterization of the murine thrombospondin gene. Lawler, J., Duquette, M., Ferro, P., Copeland, N.G., Gilbert, D.J., Jenkins, N.A. Genomics (1991) [Pubmed]
  23. Characterization of integrin beta6 and thrombospondin-1 double-null mice. Ludlow, A., Yee, K.O., Lipman, R., Bronson, R., Weinreb, P., Huang, X., Sheppard, D., Lawler, J. J. Cell. Mol. Med. (2005) [Pubmed]
  24. Thrombospondin-1 stimulates platelet aggregation by blocking the antithrombotic activity of nitric oxide/cGMP signaling. Isenberg, J.S., Romeo, M.J., Yu, C., Yu, C.K., Nghiem, K., Monsale, J., Rick, M.E., Wink, D.A., Frazier, W.A., Roberts, D.D. Blood (2008) [Pubmed]
  25. Molecular interactions that confer latency to transforming growth factor-beta. Young, G.D., Murphy-Ullrich, J.E. J. Biol. Chem. (2004) [Pubmed]
  26. Id1 regulates angiogenesis through transcriptional repression of thrombospondin-1. Volpert, O.V., Pili, R., Sikder, H.A., Nelius, T., Zaichuk, T., Morris, C., Shiflett, C.B., Devlin, M.K., Conant, K., Alani, R.M. Cancer Cell (2002) [Pubmed]
  27. Control of von Willebrand factor multimer size by thrombospondin-1. Xie, L., Chesterman, C.N., Hogg, P.J. J. Exp. Med. (2001) [Pubmed]
  28. Inhibition of angiogenesis by thrombospondin-1 is mediated by 2 independent regions within the type 1 repeats. Iruela-Arispe, M.L., Lombardo, M., Krutzsch, H.C., Lawler, J., Roberts, D.D. Circulation (1999) [Pubmed]
  29. Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. Thakar, C.V., Zahedi, K., Revelo, M.P., Wang, Z., Burnham, C.E., Barone, S., Bevans, S., Lentsch, A.B., Rabb, H., Soleimani, M. J. Clin. Invest. (2005) [Pubmed]
  30. Thrombospondin plays a vital role in the immune privilege of the eye. Zamiri, P., Masli, S., Kitaichi, N., Taylor, A.W., Streilein, J.W. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  31. Enhanced proangiogenic signaling in thrombospondin-1-deficient retinal endothelial cells. Wang, Y., Wang, S., Sheibani, N. Microvasc. Res. (2006) [Pubmed]
  32. Differential expression of thrombospondin 1, 2, and 3 during murine development. Iruela-Arispe, M.L., Liska, D.J., Sage, E.H., Bornstein, P. Dev. Dyn. (1993) [Pubmed]
  33. Thrombospondin 1 as an effective gene therapeutic strategy in collagen-induced arthritis. Jou, I.M., Shiau, A.L., Chen, S.Y., Wang, C.R., Shieh, D.B., Tsai, C.S., Wu, C.L. Arthritis Rheum. (2005) [Pubmed]
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