MATBIO-01044; No of Pages 14 Matrix Biology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Matrix Biology journal homepage: www.elsevier.com/locate/matbio Invoking the power of thrombospondins: Regulation of thrombospondins expression Olga Stenina-Adognravi ⁎ Department of Molecular Cardiology, Cleveland Clinic, 9500 Euclid Ave NB50, Cleveland, OH 44195, United States article info abstract Article history: Increasing evidence suggests critical functions of thrombospondins (TSPs) in a variety of physiological and path- Received 16 December 2013 ological processes. With the growing understanding of the importance of these matricellular proteins, the need to Received in revised form 5 February 2014 understand the mechanisms of regulation of their expression and potential approaches to modulate their levels is Accepted 8 February 2014 also increasing. The regulation of TSP expression is multi-leveled, cell- and tissue-specific, and very precise. Available online xxxx However, the knowledge of mechanisms modulating the levels of TSPs is fragmented and incomplete. This Keywords: review discusses the known mechanisms of regulation of TSP levels and the gaps in our knowledge that prevent Thrombospondin us from developing strategies to modulate the expression of these physiologically important proteins. Regulation of expression © 2014 Elsevier B.V. All rights reserved. Transcription Translation miRNA 1. Introduction important physiological and pathological processes, as well as under- standing that cells do not function in isolation from their environment Thrombospondins (TSPs) are secreted extracellular proteins that be- and ECM. long to a group of matricellular proteins — proteins that are present in The human TSP protein family consists of five members (TSP-1, TSP-2, the extracellular matrix (ECM), but do not play a primary structural TSP-3, TSP-4, and TSP-5, or cartilage oligomeric matrix protein, COMP), role as other ECM proteins do. Matricellular proteins, including TSPs, which are divided into two subgroups based on their domain structure have diverse functions that integrate ECM and cells: they interact with (Adams, 2001; Adams and Lawler, 2004, 2011) (TSP-1 and TSP-2 belong a number of cell surface receptors and with a variety of ECM proteins to subgroup A, while TSP-3, TSP-4, and TSP-5 compose subgroup B). In (e.g., structural proteins such as collagens, proteases, and growth lower organisms, TSPs are represented by a single protein, as in sponge factors). The revolutionary classification of matricellular proteins pro- (Bentley and Adams, 2010), or by multiple family members, e.g., five posedbylatePaulBornstein(Sage and Bornstein, 1991; Bornstein, proteins in sea anemone (Tucker et al., 2013), that have a structure sim- 1995) has promoted a better appreciation of ECM and its role in ilar to human TSPs of subgroup B. The second subgroup A appears later in the evolutionary development, coinciding with the development of the vascular system (Bentley and Adams, 2010), and develops further as a re- flection of the development of cardiovascular and immune systems wherethisgroupplaysanimportantrole. Abbreviations: AhR, Aryl (aromatic) hydrocarbon receptor; ARE, Adenylate-uridylate- rich element; ATF-1, Activating Transcription Factor-1; CBF, CCAAT-binding factor; COMP, Important physiological functions of TSPs have been discovered in Cartilage oligomeric matrix protein; Cyp1B1, Cytochrome P450 1B1; EBOX, Enhancer box; many organs and systems [reviewed in (Henkin and Volpert, 2011; ECM, Extracellular matrix; Egr-1, Early growth response protein 1; EGRF, Early growth re- Frangogiannis, 2012; Mayer et al., 2013; Stenina-Adognravi, 2013)]. sponse factor 1; eNOS, Endothelial nitric oxide synthase; ER, Endoplasmic reticulum; H3, Regulation of angiogenesis and cancer progression (Lawler and Histone 3; HDAC, Histone Deacetylase; HGF, Hepatocyte growth factor; HuR, Human anti- Lawler, 2012), regulation of inflammation (Frolova et al., 2010; Lopez- gen R; IR, Ischemia/reperfusion; MAPK, Mitogen-activated protein kinases; MI, Myocardial infarction; MYC, Myelocytomatosis oncogene; NO, Nitric oxide; NR4A2, Nuclear receptor Dee et al., 2011; Mustonen et al., 2012; Stenina-Adognravi, 2013; subfamily 4, group A, member 2; PAH, Pulmonary arterial hypertension; PAR-1, Vanhoutte et al., 2013), modulation of immune response (Martin- Protease-activated receptor-1; SPARC, Secreted protein acidic and rich in cysteine; TGFβ, Manso et al., 2012; Miller et al., 2013), formation of myotendinous junc- Transforming growth factor beta; TRPC4, Short transient receptor potential channel 4; tions (Subramanian et al., 2007), maintenance of the myocardium TSP, Thrombospondin; UTR, Untranslated region; WT1, Wilms' tumor suppressor; YY-1, integrity and function (Schroen et al., 2004; Chatila et al., 2007; Yin Yang 1. ⁎ Tel.: +1 216 444 9057 (office); fax: +1 216 445 8204. Swinnen et al., 2009; Cingolani et al., 2011; van Almen et al., 2011a; E-mail address: [email protected]. Frolova et al., 2012; Lynch et al., 2012; Roberts et al., 2012), regulation http://dx.doi.org/10.1016/j.matbio.2014.02.001 0945-053X/© 2014 Elsevier B.V. All rights reserved. Please cite this article as: Stenina-Adognravi, O., Invoking the power of thrombospondins: Regulation of thrombospondins expression, Matrix Biol. (2014), http://dx.doi.org/10.1016/j.matbio.2014.02.001 2 O. Stenina-Adognravi / Matrix Biology xxx (2014) xxx–xxx of fibrosis (Sweetwyne and Murphy-Ullrich, 2012), and synaptogenesis (Frolova et al., 2010). Similarly, in the wall of smaller blood vessels (Risher and Eroglu, 2012) are just a few examples of their roles in TSP-3, TSP-4, and TSP-5 not only are produced by different cell types, physiology and pathology. To participate in the critical physiological but also are deposited in ECM in distinct patterns and in distinct locali- processes, TSPs have to be present in the right location at the right zation within the vessel (Frolova, in press). In tendon, both TSP-3 and time. This review summarizes the published information about the TSP-4 are abundant, but are arranged in fibers of different orientations, regulation of the expression of TSPs. stressing the distinctions in their functions (Frolova, in press). When TSPs are expressed in the same structures at the same time [e.g., TSP-4 2. Similarities and distinctions between TSP family members and TSP-5 in tendon (Frolova, in press)], it is still unclear why both are required and what differential properties of tissue they support. All TSPs share a high degree of homology at the protein level, espe- Differences in the expression profiles of individual TSPs in cancers cially in their “signature domain”—the C-terminal half of the human and other cells and tissues [e.g., (Carron et al., 2000; Agah et al., 2002; protein that includes 3–4EGF-likerepeats[1–5 in other species Bornstein et al., 2004)] suggest that TSPs have differential functions in (Adams and Lawler, 2011)], the Ca2+-binding domains with up to 26 pathological processes, despite shared homologous domains and li- metal binding sites per protein subunit, and the globular C-terminal do- gands. Several gene expression studies demonstrated opposite profiles main [reviewed in (Adams and Lawler, 2011)]. Table 1 summarizes the for TSP-1 and TSP-4 in brain (Bredel et al., 2005; Liang et al., 2005; extent of homology between five TSPs. However, apart from the protein Sun et al., 2006) and breast (Sorlie et al., 2001; Turashvili et al., 2007; coding regions of the TSP genes (THBS), there is no homology in their Ma et al., 2009) cancers. Examination of the datasets from these studies DNA sequence, and the regulatory parts of TSP genes, either the reveals that TSP-4 upregulation is accompanied by downregulation of untranslated regions of mRNA (UTR) or the gene promoters, are dis- TSP-1 in the tumor samples (www.oncomine.org), clearly indicating tinctly different at the first glance (Adolph et al., 1997). Search for com- distinct, probably even opposite, functions for these two proteins. Unex- mon DNA sequence motifs using SCOPE motif finder (http://genie. pectedly, TSP-2, belonging to subgroup A and sharing high homology dartmouth.edu/scope)(Carlson et al., 2007; Chakravarty et al., 2007) with TSP-1, exhibits a profile similar to the TSP-4 profile — it is upregu- and comparison of the positions of common DNA sequence motifs in lated in both brain and breast cancers, with the exception of one data set the promoters of five TSPs reveal some similarities between TSP pro- (Bredel et al., 2005). In some datasets TSP-2 was in top 1% of upregulat- moters and suggest that in some conditions two or more TSPs may be ed genes, together with TSP-4. These comparisons of the three TSP pro- regulated by the same stimuli simultaneously (Fig. 1). However, there files from the same datasets clearly demonstrate that the three TSPs are no experimental data to support the predicted similarity of the play important distinct roles in cancer growth, and the regulation of DNA motifs. their expression is an efficient mechanism to support these still poorly The five proteins are located on different chromosomes (human understood functions (with the exception of TSP-1, whose downregula- THBS1 on chromosome 15 and mouse Thbs1 on chromosome 2, tion is known to support angiogenesis in tumors). TSP-5 was upregulat- human THBS2 on chromosome 6 and mouse Thbs2 on chromosome ed similar to TSP-4 in multiple datasets from breast cancer studies 17, human THBS3 on chromosome 1 and mouse Thbs3 on chromosome (www.oncomine.org), while TSP-3 data were inconsistent, and both 3, human THBS4 on chromosome 5 and mouse Thbs4 on chromosome 13, down-regulation and up-regulation were observed (Ramaswamy human THBS5 on chromosome 19 and mouse Thbs5 on chromosome 8). et al., 2003; Yu et al., 2008). In most tissues, TSPs are expressed at a low level compared to other The expression studies in human samples and in animal tissues non-structural ECM proteins, e.g., SPARC, tenascin C and fibronectin clearly suggest distinct functions and roles in physiological and patho- (Fig.