Disease relevance of THBS1

• CIMP+ tumors also have a high incidence of p16 and THBS1 methylation, and they include the majority of sporadic colorectal cancers with microsatellite instability related to hMLH1 methylation [1].
• Further studies showed THBS1 expression was sensitive to pertussis toxin and protein kinase C inhibition indicating G(i/o)- and G(q)-mediated pathways [2].
• Decreased expression of Thrombospondin-1 (THBS1), a P53 and Rb regulated angiogenesis inhibitor, has been observed in some human tumors, including glioblastoma multiforme (GBM) [3].
• The involvement of CPE and THBS1 in obesity allows us to suggest that the physiological processes controlled by these genes contribute to depot and gender-related differences in the metabolic complications of obesity [4].
• HRGP colocalized with TSP-1 in the stroma of human breast cancer specimens, and this interaction masked the antiangiogenic epitope of TSP-1 [5].

Psychiatry related information on THBS1

• In CJD patients the HS level was almost double that of the TSP/HAM patients [6].
• TSP/HAM is a chronic motor disease that affects the white matter of the spinal cord, while CJD is a subacute dementia that affects cerebral neurons and their synapsis [6].
• In many reptile species, sexual differentiation of gonads is sensitive to temperature (temperature-dependent sex determination, TSD) during a critical period of embryonic development (thermosensitive period, TSP) [7].
• The distribution of thrombospondin staining in patients with Alzheimer's disease was found to be comparable to control subjects [8].
• RESULTS: Both the HTLV-1 carrier group and the group of patients with TSP/HAM exhibited a lower performance in neuropsychological tests when compared with controls [9].

High impact information on THBS1

• The human T cell leukemia virus-1 (HTLV-1) is a retrovirus that causes adult T cell leukemia (ATL) and neurological disorder, the tropical spastic paraparesis (HAM/TSP) [10].
• These antibodies reacted only with the surface of MC strain PEs and blocked adherence of these cells to CD36 but without effect on adherence to thrombospondin [11].
• This interaction is inhibited by anti-PADGEM antibodies, PADGEM, and EDTA; anti-GPIIb-IIIa, anti-thrombospondin, anti-GPIV, and thrombospondin produce no effect [12].
• While parasitized erythrocytes have been shown to specifically bind to the platelet/matrix molecule thrombospondin, adherence to suitable target cells can also be blocked by monoclonal antibody OKM5, which recognizes a surface molecule expressed by hematopoietic cells and endothelium [13].
• Here we report that expression of a CD36 cDNA clone in COS cells supports cytoadherence of parasitized erythrocytes but does not support increased binding of purified human thrombospondin [13].

Chemical compound and disease context of THBS1

• Thrombospondin (TSP) is a Mr 450,000 multifunctional matrix glycoprotein that interferes with tumor growth, angiogenesis, and metastasis [14].
• Adhesion of osteosarcoma cells to the 70-kDa core region of thrombospondin-1 is mediated by the alpha 4 beta 1 integrin [15].
• Effects of 17beta-estradiol, progesterone, synthetic progestins, tibolone, and raloxifene on vascular endothelial growth factor and Thrombospondin-1 messengerRNA in breast cancer cells [16].
• Induction of thrombospondin-1 by all-trans retinoic acid modulates growth and differentiation of HL-60 myeloid leukemia cells [17].
• MATERIALS/METHODS: The expression of TSP-1 was studied in formalin fixed, paraffin wax embedded sections from 58 cases of pure DCIS, using a monoclonal antibody against TSP-1 and the avidin-biotin-diaminobenzidine immunoperoxidase detection system [18].

Biological context of THBS1

• We have recently described a novel pathway termed CpG island methylator phenotype (CIMP) in CRC, which is characterized by the simultaneous methylation of multiple CpG islands, including several known genes, such as p16, hMLH1, and THBS1 [19].
• Thrombospondin-1 (THBS1) is a large extracellular matrix glycoprotein that affects vasculature systems such as platelet activation, angiogenesis, and wound healing [2].
• THBS1 up-regulation was also confirmed in human umbilical vein endothelial cells stimulated with thrombin [2].
• The present study focuses on the effects of thrombin activation of the G-protein-coupled, protease-activated receptor-1 (PAR-1) on THBS1 gene expression in the microvascular endothelium [2].
• Analysis of the promoter region of THBS1 and other genes of similar expression profile identified from the microarray predicted an EBOX/EGRF transcription model [2].

Anatomical context of THBS1

• To study whether methylation-associated inactivation is involved in down-regulating THBS1 expression in cancer, we analysed the methylation status of THBS1 in several cell lines and primary tumors [3].
• We also examined the roles of THBS1 and CTGF in mediating high-glucose- and glycated-albumin-induced synthesis of the matrix protein, fibronectin, by mesangial cells [20].
• METHODS: The effects of VDRAs on regulating PAI-1, THBS1 and TM in human aortic smooth muscle cells (SMC) and endothelial cells (EC) were studied [21].
• BACKGROUND: Thrombospondin-1 (TSP) is a 430-kd glycoprotein that is an important component of the extracellular matrix and is known to be a potent inhibitor of angiogenesis (i.e., formation of new blood vessels) both in vitro and in vivo [22].
• TSP expression was an independent predictor of disease recurrence (P = .002) and overall survival (P = .01) after stratifying for tumor stage, lymph node status, and histologic grade, but it was not independent of p53 status [22].

Associations of THBS1 with chemical compounds

• In contrast to THBS1, CTGF is required for mesangial synthesis of fibronectin stimulated by high glucose or glycated albumin, and is thus a potential therapeutic target [20].
• Determination of THBS1 gene structure has revealed that the type I repeat modules are encoded by symmetrical exons and that the heparin-binding domain is encoded by a single exon [23].
• A recombinant piece of TSP2 containing this sequence replicated the alpha4beta1 integrin-dependent activities of TSP1 [24].
• The enhanced spreading induced by TS1 and 4N1K and the constitutive spreading on higher density VN are both blocked by calphostin C (100 nM), wortmannin (10 nM), and tyrosine kinase inhibitors [25].
• With this assay we assessed the binding of TS in solution to proteins adsorbed to polystyrene microtiter plates [26].
• New research has identified components downstream of NO as the primary target of the endogenous angiogenesis inhibitor thrombospondin-1 and has shown that circulating levels of thrombospondin-1 are sufficient to limit angiogenic responses by antagonizing NO signaling [27].
• The formation of cis and trans dimers of the TSPN-1 domain with relatively short segments of heparin further enhances the ability of TSP-1 to participate in high affinity binding to glycosaminoglycans [28].

Physical interactions of THBS1

• Platelet thrombospondin forms a trimolecular complex with plasminogen and histidine-rich glycoprotein [29].
• We have shown previously that HRGP binds with high affinity to thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that is a potent inhibitor of angiogenesis [5].
• PAS-IV bound to TSP with similar characteristics except that maximum binding was consistently approximately 50% of that of GPIIIb and binding was not inhibited by EDTA [30].
• We investigated the mechanism by which TS-bound IAP modulates the affinity of platelet integrin, alphaIIbbeta3 [31].
• Peptides spanning aa 19-36 (RWIESKHKSDFGKFVLSS) blocked hep I-stimulated focal adhesion disassembly, indicating that the TSP/hep I-binding site is located to this sequence in calreticulin [32].
• Gel shift and antibody supershift studies indicated that ATF-1 was involved in DNA binding to the TSP-1-CRE site [33].

Enzymatic interactions of THBS1

• Thrombospondin was cleaved by neutrophil elastase, but the site(s) of the limited cleavage are independent of the competitive inhibition of elastase activity by thrombospondin [34].

Regulatory relationships of THBS1

• Results of an analysis of variance were compatible with the hypothesis that p53 affects tumor angiogenesis by regulating the level of TSP expression [22].
• Fibronectin also enhanced TSP1 binding to purified alpha3beta1 integrin [35].
• However, the CD47-activated SS RBC adhesion receptor(s) that mediated adhesion to immobilized TSP remained unknown [36].
• Using an enzyme-linked immunosorbent assay and a TSP-Sepharose affinity bead-binding assay we have found that Plg-TSP complex formation was markedly enhanced (up to 5-fold) when catalytic concentrations of Plg activators were included in the reaction mixtures [37].
• A peptide from thrombospondin 1 modulates experimental erosive arthritis by regulating connective tissue growth factor [38].

Other interactions of THBS1

• The antiangiogenic activity of TSP-1 is mediated by the binding of properdin-like type I repeats to the receptor CD36 [5].
• TSP expression was significantly associated with p53 expression status (P = .001) and microvessel density counts (P = .001) [22].
• Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator [39].
• Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1 [5].
• We found that binding of HRGP to TSP-1 was similarly mediated by TSP type I repeats [5].

Analytical, diagnostic and therapeutic context of THBS1

• Three cell lines (RKO, CEM and RAJI) were completely methylated at several CpG sites within the THBS1 5' CpG island, and had no detectable expression by RT-PCR [3].
• TSP also formed a complex with plasmin as detected by ELISA but did not directly inhibit plasmin activity measured with a synthetic fluorometric substrate or with a 125I-fibrin plate assay [39].
• Metabolic labeling of glial cell cultures with [35S]methionine followed by immunoprecipitation with monospecific anti-thrombospondin revealed synthesis of a 180-kDa polypeptide that comigrated with platelet thrombospondin on NaDodSO4/PAGE [40].
• Heparin-Sepharose affinity chromatography of material derived from a human brain homogenate yielded a protein that, when reduced, had an apparent size of 180 kDa and comigrated with reduced platelet thrombospondin on NaDodSO4/PAGE [40].
• Indirect immunofluorescence of cultured human glial cells indicated the presence of thrombospondin [40].

References