Invoking the power of thrombospondins: Regulation of thrombospondins expression

Abstract

Increasing evidence suggests critical functions of thrombospondins (TSPs) in a variety of physiological and pathological processes. With the growing understanding of the importance of these matricellular proteins, the need to understand the mechanisms of regulation of their expression and potential approaches to modulate their levels is also increasing. The regulation of TSPs expression is multi-leveled, cell- and tissue-specific, and very precise. However, the knowledge of mechanisms modulating the levels of TSPs is fragmented and incomplete. This review discusses the known mechanisms of regulation of TSPs levels and the gaps in our knowledge that prevent us from developing strategies to modulate the expression of these physiologically important proteins.

Thrombospondin-1, -2 and -5 have differential effects on vascular smooth muscle cell physiology

“…The TSP family consists of 5 member proteins, which are divided into Groups A (TSP-1, TSP-2) and B (TSP-3, TSP-4, TSP-5), determined by the inclusion (Group A) or exclusion (Group B) of Type 1 repeats, domains found at the N-terminal side of the molecules [3]. TSP-1 is the most studied TSP, and is established as a potent anti-angiogenic protein [4] and an inducer of VSMC chemotaxis and proliferation [5].…”

Expression of thrombospondin-1 by tumor cells in patient-derived ovarian carcinoma xenografts

“…TSP-1 expression did not correlate with the expression of p53 in our panel of PDX, as well as in the external database analyzed. A lack of correlation between p53 status and TSP-1 expression has been reported in different tumor types (35)(36)(37), indicating that the exact role of p53 in regulating tumor TSP-1 is still debatable, and other factors, including transcription factors and microRNAs, might contribute to regulate TSP-1 expression in a cell-and context-dependent manner (38)(39)(40). TSP-1 expression was not associated with p53 expression in patients with ovarian cancer analyzed for expression of angiogenesis regulatory factors (21,22), suggesting that TSP-1 expression is not regulated by p53 in this tumor type.…”

Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation

“…The potential importance of variation in the 5′-and 3′-UTRs should also not be underestimated, as our understanding grows of how the secondary structure of these UTR can affect transcript stability, for example, by miRNA-mediated degradation (55), and also regulate the translational machinery (56). In support of the importance of UTR regions in matricellular protein expression, TSP-1 in particular has a long 3′ UTR that has been analysed in detail, and is known to contain AU-rich elements that regulate mRNA stability (17). Indeed, the regulation of TSP-1 expression by glucose occurs at the level of translation and is mediated by miR-467 binding to the 3′-UTR (57,58).…”

“…SPARC similarly regulates signalling by a number of growth factors, both directly and indirectly, including TGFβ, VEGF, PDGF, FGF and HGF (14,15). TGFβ in turn regulates the expression of a number of matricellular proteins, including SPARC, CCN1, TSP-1, TSP-2 and POSTN (16)(17)(18)(19).…”

“…Therefore while the majority of evidence suggests a pathogenic role for SPARC in diabetes, it remains possible that under some circumstances SPARC may have beneficial effects in β cells. Similarly, TSP-1 expression in islet endothelial cells is important for islet function (40), and metabolic parameters such as high glucose also regulate TSP-1 expression (17). As for SPARC, elevated adipose expression of OPN also occurs in obesity, and is thought to predispose to insulin resistance (41).…”