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Gene Review

Thbs1  -  thrombospondin 1

Rattus norvegicus

Synonyms: TSP-1, Tsp1
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Disease relevance of Thbs1


High impact information on Thbs1


Chemical compound and disease context of Thbs1


Biological context of Thbs1

  • We previously showed that inducible expression of the catalytic domain of cGMP-dependent protein kinase (PKG) inhibits glucose-regulated TSP1 transcription and transforming growth factor (TGF)-beta activity in stably transfected rat mesangial cells (RMCs(tr/cd)) [12].
  • Using a luciferase-promoter deletion assay, we now identify a single region of the human TSP1 promoter (-1172 to -878, relative to the transcription start site) that is responsive to glucose [12].
  • MC displayed a single class of heparin-inhibitable TSP binding sites (Bmax 3.8 +/- 1.8 x 10(6)/cell, Kd = 80 +/- 29 nM) [13].
  • Since little is known about signal transduction pathways regulating TSP expression in liver, we investigated cytokine-mediated upregulation of TSP-1 and TGF-beta1 in primary rat hepatic stellate cells (HSC) [14].
  • Mesangial cell upregulation of TSP-1 is associated with migration and proliferation but not maximal ECM accumulation, whereas mesangial cell expression of Fn-EIIIA is associated with proliferation and ECM accumulation [15].

Anatomical context of Thbs1


Associations of Thbs1 with chemical compounds

  • However, the molecular mechanisms by which PKG represses glucose-regulated TSP1 transcription are unknown [12].
  • Thrombospondin (TSP) is an extracellular matrix glycoprotein involved in mesangial cell (MC) adhesive and migratory function [13].
  • Based on these observations, we propose the existence of an autocrine positive feedback loop of MC proliferation involving TSP and growth factors, and regulated by heparan sulfate [13].
  • TSP, in a concentration dependent manner (5 to 20 micrograms/ml), caused an increase in thymidine uptake, first detectable at 28 hours and more prominent at 48 hours [13].
  • Moreover, Ang II induction of TSP1 and increased TGF-beta activity were blocked by losartan, an antagonist of the Ang II type 1 (AT1) receptor [1].

Physical interactions of Thbs1


Regulatory relationships of Thbs1

  • TSP induced epidermal growth factor (EGF) secretion and significantly augmented constitutive platelet-derived growth factor-AB (PDGF-AB) secretion by MC in a concentration dependent fashion [13].
  • Fusion constructs of the type 1, 2, and 3 repeats and the COOH terminus of TSP1 were tested for their ability to activate latent TGF-beta [18].
  • Immunocytochemistry for extracellular matrix molecules showed that microglial cells stained positively for growth-promoting thrombospondin, whereas laminin and the inhibitory chondroitin sulfate proteoglycans (CSPGs) were localized primarily to SC [19].

Other interactions of Thbs1


Analytical, diagnostic and therapeutic context of Thbs1

  • TSP-1 mRNA expression was investigated using a radioactive in situ hybridization technique [2].
  • Northern and Western blot analysis were used to study the temporal profile of TSP-1 and TSP-2 expression at the mRNA and protein level, respectively [3].
  • We found that TGF-beta1 enhanced production and secretion of TSP, with peak levels of secreted TSP observed 24 h after treatment [17].
  • In summary, these studies support the hypothesis that TGF-beta-induced JNK1 activation and proliferation of RASMC require secretion of TSP and ligation of alpha(v)beta(3)-integrins [17].
  • Thrombospondin was localized in osteoid of undemineralized, frozen sections of fetal subperiosteal bone, and identified as a component of mineralized bone matrix of neonatal and/or young (growing) bone of many animal species by Western blot analysis [24].


  1. Thrombospondin 1 mediates angiotensin II induction of TGF-beta activation by cardiac and renal cells under both high and low glucose conditions. Zhou, Y., Poczatek, M.H., Berecek, K.H., Murphy-Ullrich, J.E. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  2. Sustained expression of thrombospondin-1 is associated with the development of glomerular and tubulointerstitial fibrosis in the remnant kidney model. Hugo, C., Kang, D.H., Johnson, R.J. Nephron (2002) [Pubmed]
  3. Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion. Lin, T.N., Kim, G.M., Chen, J.J., Cheung, W.M., He, Y.Y., Hsu, C.Y. Stroke (2003) [Pubmed]
  4. Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat. Hugo, C., Shankland, S.J., Pichler, R.H., Couser, W.G., Johnson, R.J. Kidney Int. (1998) [Pubmed]
  5. F-spondin: a gene expressed at high levels in the floor plate encodes a secreted protein that promotes neural cell adhesion and neurite extension. Klar, A., Baldassare, M., Jessell, T.M. Cell (1992) [Pubmed]
  6. 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]
  7. Identification of integrin alpha 3 beta 1 as a neuronal thrombospondin receptor mediating neurite outgrowth. DeFreitas, M.F., Yoshida, C.K., Frazier, W.A., Mendrick, D.L., Kypta, R.M., Reichardt, L.F. Neuron (1995) [Pubmed]
  8. Inhibition of retinal angiogenesis by peptides derived from thrombospondin-1. Shafiee, A., Penn, J.S., Krutzsch, H.C., Inman, J.K., Roberts, D.D., Blake, D.A. Invest. Ophthalmol. Vis. Sci. (2000) [Pubmed]
  9. Kinetics of biglycan, decorin and thrombospondin-1 in mercuric chloride-induced renal tubulointerstitial fibrosis. Suzuki, K., Wang, R., Kubota, H., Shibuya, H., Saegusa, J., Sato, T. Exp. Mol. Pathol. (2005) [Pubmed]
  10. Expression of constitutively active cGMP-dependent protein kinase prevents glucose stimulation of thrombospondin 1 expression and TGF-beta activity. Wang, S., Wu, X., Lincoln, T.M., Murphy-Ullrich, J.E. Diabetes (2003) [Pubmed]
  11. Androgens repress the expression of the angiogenesis inhibitor thrombospondin-1 in normal and neoplastic prostate. Colombel, M., Filleur, S., Fournier, P., Merle, C., Guglielmi, J., Courtin, A., Degeorges, A., Serre, C.M., Bouvier, R., Clézardin, P., Cabon, F. Cancer Res. (2005) [Pubmed]
  12. Glucose up-regulates thrombospondin 1 gene transcription and transforming growth factor-beta activity through antagonism of cGMP-dependent protein kinase repression via upstream stimulatory factor 2. Wang, S., Skorczewski, J., Feng, X., Mei, L., Murphy-Ullrich, J.E. J. Biol. Chem. (2004) [Pubmed]
  13. Role of thrombospondin in mesangial cell growth: possible existence of an autocrine feedback growth circuit. Marinides, G.N., Suchard, S.J., Mookerjee, B.K. Kidney Int. (1994) [Pubmed]
  14. Characterization of intracellular pathways leading to coinduction of thrombospondin-1 and TGF-beta1 expression in rat hepatic stellate cells. Breitkopf, K., Sawitza, I., Gressner, A.M. Growth Factors (2005) [Pubmed]
  15. Differential expression of thrombospondin and cellular fibronectin during remodeling in proliferative glomerulonephritis. Barnes, J.L., Mitchell, R.J., Kanalas, J.J., Barnes, V.L. J. Histochem. Cytochem. (1999) [Pubmed]
  16. A CD36 synthetic peptide inhibits bleomycin-induced pulmonary inflammation and connective tissue synthesis in the rat. Yehualaeshet, T., O'Connor, R., Begleiter, A., Murphy-Ullrich, J.E., Silverstein, R., Khalil, N. Am. J. Respir. Cell Mol. Biol. (2000) [Pubmed]
  17. Autocrine thrombospondin partially mediates TGF-beta1- induced proliferation of vascular smooth muscle cells. Sajid, M., Lele, M., Stouffer, G.A. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
  18. The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-beta. Schultz-Cherry, S., Lawler, J., Murphy-Ullrich, J.E. J. Biol. Chem. (1994) [Pubmed]
  19. Microglia enhance dorsal root ganglion outgrowth in Schwann cell cultures. Hynds, D.L., Rangappa, N., Ter Beest, J., Snow, D.M., Rabchevsky, A.G. Glia (2004) [Pubmed]
  20. Thrombospondin-1 is a major activator of TGF-beta in fibrotic renal disease in the rat in vivo. Daniel, C., Wiede, J., Krutzsch, H.C., Ribeiro, S.M., Roberts, D.D., Murphy-Ullrich, J.E., Hugo, C. Kidney Int. (2004) [Pubmed]
  21. 1,25-dihydroxyvitamin D inhibits renal interstitial myofibroblast activation by inducing hepatocyte growth factor expression. Li, Y., Spataro, B.C., Yang, J., Dai, C., Liu, Y. Kidney Int. (2005) [Pubmed]
  22. Induction of transforming growth factor-beta autocrine activity by all-trans-retinoic acid and 1 alpha,25-dihydroxyvitamin D3 in NRP-152 rat prostatic epithelial cells. Danielpour, D. J. Cell. Physiol. (1996) [Pubmed]
  23. Changes in the immunohistochemical localisation of fibroblast growth factor-2, transforming growth factor-beta 1 and thrombospondin-1 are associated with early angiogenic events in the hyperplastic rat thyroid. Patel, V.A., Hill, D.J., Eggo, M.C., Sheppard, M.C., Becks, G.P., Logan, A. J. Endocrinol. (1996) [Pubmed]
  24. Thrombospondin is an osteoblast-derived component of mineralized extracellular matrix. Robey, P.G., Young, M.F., Fisher, L.W., McClain, T.D. J. Cell Biol. (1989) [Pubmed]
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