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abbr. TSP2; gene symbol THBS2. This protein has been identified by LaBell et al (1992) by sequence homology of its cDNA towards human thrombospondin-1. Thrombospondin-2 and related proteins are characterized by a number of protein domains known as thrombospondin type 1 repeats, thrombospondin type 2 repeats, thrombospondin type 2 repeats.
The TSP2 gene is expressed in fibroblasts, smooth muscle cells, an osteosarcoma cell line, and Swiss 3T3 cells, but not in umbilical vein endothelial cells. The protein can form heterotrimeric complexes with thrombospondin (O'Rourke et al, 1992). Unlike thrombospondin, thrombospondin-2 expression is not upregulated by serum in murine NIH 3T3 cells (Bornstein et al, 1991).
Kyriakides et al (1998) have generated knock-out mice lacking expression of thrombospondin-2. Mutant mice are fertile. They show abnormalities in connective tissue structure and function (fragile skin with reduced tensile strength, unusually flexible tail). The mutant mice also have increased thickness and density of cortical bones, significantly increased densities in small blood vessels and abnormally long bleeding times, despite normal blood coagulation and the lack of thrombocytopenia. Kyriakides et al (1999) have reported also that mice lacking thrombospondin-2 shoiw accelerated wound healing processes. Kokenyesi et al (2004) have reported that Thrombospondin-2 deficiency in pregnant mice results in premature softening of the uterine cervix, which is accompanied by increased levels of the matrix metalloproteinase MMP-2. Kyriakides et al (2003) have reported that the uptake of thrombospondin-2 by megakaryocytes is required for normal platelet formation and function.
Streit et al (1999) have demonstrated that thrombospondin-2 is a potent endogenous inhibitor of tumor growth and angiogenesis. Several studies have reported that the lack of thrombopondin-2 expression correlates with enhanced angiogenesis and vascularity, for example, in gliomas (Kazuno et al, 1999), metastatic colon cancers (Tokunaga et al, 1999), non-small cell lung cancer (Oshika et al, 1998). Noh et al (2003) have used a recombinant 80 kDa N-terminal fragment of human TSP-2 (TSP-2/NTF) to study the potential antitumoral efficacy of systemic thrombospondin-2 therapy. Daily intraperitoneal injections of this fragment into nude mice bearing human A431 squamous cell carcinoma cells as xenotransplants reduces tumor vascularization. In vitro, this fragment inhibits the migration of human dermal microvascular endothelial cells induced by VEGF, and inhibits tube formation on Matrigel in vitro. The fragment also inhibits angiogenesis induced by VEGF in an in vivo Matrigel assay. In addition, the 80 kDa fragment potently induces cell death by apoptosis of human dermal microvascular endothelial cells in vitro, but does not affect A431 tumor cell proliferation or apoptosis. Hawighorst et al (2001) have reported that thrombospondin-2 deficiency dramatically enhances susceptibility to chemical skin carcinogenesis and results in accelerated and increased tumor formation, which is accompanied by significantly enhanced tumor angiogenesis and reduction of tumor cell apoptosis.
Park et al (2004) have shown that TSP2 produced by synovial fibroblasts, endothelial cells, and macrophages correlates with the intensity of angiogenesis and with the architecture of lymphoid infiltrates in rheumatoid arthritis. Overexpression of TSP2 causes an inhibition of lesional vascularization, suppresses the production of the pro-inflammatory cytokines IFN-gamma and TNF-alpha, and induces the depletion of tissue-residing T-cells.
Thrombospondin-2 inhibits the growth of human microvascular endothelial cells mediated by bFGF, IGF-1, EGF, and VEGF. This is due, at least in part, to two independent processes, namely, the inhibition of cell cycle progression and the induction of cell death (Armstrong et al, 2002).
Hankenson and Bornstein (2002) have reported that secreted thrombospondin-2 is an autocrine inhibitor of bone marrow stromal cell proliferation.
The bovine homolog of thrombospondin-2 has been identified as CISP [corticotropin-induced secreted protein], the secretion of which into the conditioned medium of bovine adrenocortical cells is observed after treatment with ACTH (Pellerin et al, 1993). Expression is upregulated also by Activin A and TGF-beta (Negoescu et al, 1994). CISP has an effect on the migration of adrenocortical cells and inhibits cell spreading (Pellerin et al, 1994). Volpert et al (1995) have reported that CISP inhibits the migration of capillary endothelial cells towards a variety of inducers and also inhibits neovascularization induced in the rat cornea.
See also: Angiogenesis Dictionary section of this encyclopedia for other entries directly bearing on factors and processes involved in the generation of new blood vessels.
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ENTRY LAST MODIFIED: March 2005
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