Sequence and Characterization of the Complete Human Thrombospondin 2 cDNA: Potential Regulatory Role for the 3′ Untranslated Region

Labell, Terry L.; Byers, Peter H.

doi:10.1006/geno.1993.1308

Cited by 30 publications

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“…1), with only one gap, to the 3Ј-untranslated region of the human mRNA encoding Tsp-1 (33). In mammals, there are at least five highly homologous tsp genes (34); however, their 3Ј-untranslated regions are quite dissimilar (35). This 3Ј-terminal diversity allowed us to conclude that we had cloned the 3Ј end of the avian tsp-1 gene, rather than tsp-2 or -4, which had been previously identified in avian species (36,37).…”

Section: Resultsmentioning

confidence: 99%

Viral Myc Oncoproteins in Infected Fibroblasts Down-modulate Thrombospondin-1, a Possible Tumor Suppressor Gene

Tikhonenko

Black²,

Linial

1996

Journal of Biological Chemistry

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We are interested in identifying the transcriptional targets of the Myc oncoproteins. To this end, we have fused Myc of the MC29 retrovirus with the rat glucocorticoid receptor. This chimeric protein requires dexamethasone to undergo nuclear translocation and achieve an active conformation. We employed a differential hybridization approach to identify mRNAs that are induced or repressed in infected avian fibroblasts in response to dexamethasone. This screen yielded one mRNA underrepresented in the dexamethasone-treated cells. In Myc-transformed cell clones, its level decreases 6-fold as early as 4 h and more than 30-fold after 32 h of exposure to the hormone. This mRNA was also downregulated by recombinant Myc retroviruses in rodent fibroblasts, including those refractory to transformation.Sequence analysis revealed that it is homologous to the 3 untranslated regions of the mammalian thrombospondin-1 genes. Using an anti-thrombospondin antibody, we confirmed that rodent cells overexpressing Myc produce very small amounts of this protein. Also, they do not support efficient expression of a reporter gene driven by the thrombospondin-1 promoter. Thus, thrombospondin-1 is a bona fide target of Myc. Moreover, its silencing might pertain to the transforming activity of Myc, since in several systems thrombospondin-1 exhibits tumor suppressor properties, presumably due to its negative effect on neovascularization.

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Section: Resultsmentioning

confidence: 99%

Viral Myc Oncoproteins in Infected Fibroblasts Down-modulate Thrombospondin-1, a Possible Tumor Suppressor Gene

Tikhonenko

Black²,

Linial

1996

Journal of Biological Chemistry

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“…Among the TSP subtypes, TSP-2 showed considerable protein sequence similarity to that of TSP-1 which is known to be functionally critical. TSP-1 and TSP-2 are clearly distinct gene products (Labell et al, 1993), although both modulate angiogenesis (Volpert et al, 1995). TSP-2 blocks the migration of capillary endothelial cells evoked by a variety of inducers, and inhibits neovascularization in the rat cornea (Panetti et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…TSP induces platelet aggregation (Legrand et al, 1992) and inhibits angiogenesis (Iruela et al, 1991;Weinstat et al, 1994). There are five subtypes of TSPs, namely TSP-1, TSP-2 (Labell et al, 1993), TSP-3 (Vos et al, 1992), TSP-4 (Lawler et al, 1993) and cartilage oligomeric matrix protein (Oldberg et al, 1992). Of the five structurally different TSPs, TSP-1 and TSP-2 show similarities in their molecular architecture and modulatory effects on angiogenesis Bornstein et al, 1992;Laherty et al, 1992).…”

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Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer

et al. 1998

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Summary Two subtypes of thrombospondin (TSP-1 and TSP-2) have inhibitory roles in angiogenesis in vitro, although the biological significance of these TSP isoforms has not been determined in vivo. We examined TSP-1 and TSP-2 gene expression by reverse transcription polymerase chain reaction (RT-PCR) analysis in 61 colon cancers. Thirty-eight of these 61 colon cancers were positive for TSP-2 expression and showed hepatic metastasis at a significantly lower incidence than those without TSP-2 expression (P = 0.02). TSP-2 expression was significantly associated with M0 stage in these colon cancers (P = 0.03), whereas TSP-1 expression showed no apparent correlation with these factors. The colon cancer patients with TSP-2 expression showed a significantly low frequency of liver metastasis correlated with the cell-associated isoform of vascular endothelial growth factor (VEGF-189) (P = 0.0006). Vascularity was estimated by CD34 staining, and TSP-2(-)/VEGF-189(+) colon cancers showed significantly increased vessel counts and density in the stroma (P < 0.0001). TSP-2(-)/VEGF-189(+) colon cancer patients also showed significantly poorer prognosis compared with those with TSP-2(+) / VEGF-189(-) (P = 0.0014). These results suggest that colon cancer metastasis is critically determined by angiogenesis resulting from the balance between the angioinhibitory factor TSP-2 and angiogenic factor VEGF-189.

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“…If these active sequences are critical for cell attachment to the N-terminal domain of human TSP-1, then one would expect these residues to be conserved within human TSP-2. Although the N-terminal domain of human TSP-1 is only 37 % identical with human TSP-2 [38], a higher degree of homology exists between TSP-1 and TSP-2 between residues 60 and 94 (48 % identity) and 189-200 (67 % identity) ( Figure 7). Moreover, these two cell adhesive sites are also highly conserved in all known species of TSP (mouse TSP-1, mouse TSP-2 and chicken TSP-2) (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

Identification of cell adhesive active sites in the N-terminal domain of thrombospondin-1

Clézardin

Lawler

Amiral³

et al. 1997

Biochemical Journal

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Using a series of fusion proteins that span almost all of the thrombospondin-1 (TSP-1) molecule, we observed in this study that Chinese hamster ovary (CHO) K1 cells strongly attached to the N-terminus but not to the other domains of TSP-1 (e.g. the C-terminus, and type 1, type 2 and type 3 repeats). In addition, attachment to the N-terminus of CHO S745 cells defective in cellsurface glycosaminoglycans (GAGs) was decreased by 47 % compared with that observed with CHO K1 cells, indicating the presence of GAG-dependent cell adhesive sites. With the aim of identifying these cell adhesive sites, a series of synthetic peptides, overlapping heparin-binding sequences ARKGSGRR (residues 22-29), MKKTRG (residues 79-84) and TRDLASIARLRIA-KGVNDNF (residues 170-189), were synthesized and tested for their ability to support CHO cell attachment. Using both centrifugation and cell-attachment assays, MKKTRG-containing peptides promoted CHO K1 cell adhesion, while ARKGSGRR-containing peptides and peptide TRDLASIARL-RIAKGVNDNF did not. CHO S745 cell attachment to MKKTRG-containing peptides was partially decreased. A 36 % decrease in CHO K1 cell attachment to the N-terminus was also observed when the heparin-binding consensus sequence KKTR was mutated to QNTR. In addition, peptide MKKTRG partially inhibited (25 % inhibition) CHO K1 cell attachment to the Nterminus. However, peptide MKKTRG was not sufficient to

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Sequence and Characterization of the Complete Human Thrombospondin 2 cDNA: Potential Regulatory Role for the 3′ Untranslated Region

Cited by 30 publications

References 0 publications

Viral Myc Oncoproteins in Infected Fibroblasts Down-modulate Thrombospondin-1, a Possible Tumor Suppressor Gene

Viral Myc Oncoproteins in Infected Fibroblasts Down-modulate Thrombospondin-1, a Possible Tumor Suppressor Gene

Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer

Identification of cell adhesive active sites in the N-terminal domain of thrombospondin-1

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