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PubMed2001

Isolation of a cDNA encoding a putative SPARC from the brine shrimp, Artemia franciscana.

SPARC (Secreted protein, acidic, rich in cysteine) is an extracellular matrix-associated and anti-adhesive glycoprotein extensively studied in vertebrates. Its presence among invertebrates has been reported in nematodes and flies. We cloned a cDNA containing a complete open reading frame for SPARC from the brine shrimp, Artemia franciscana. The amino acid sequence identity between the Artemia and the fly SPARCs was 55%, whereas that of the Artemia and the nematode proteins was 45%. Artemia and vertebrates exhibited a sequence identity of 30% in the predicted aa sequences. The SPARC consisted of four domains commonly found among reported SPARCs. The protein comprised 291 amino acids, having a signal peptide, a follistatin-like domain, one N-glycosylation site and one calcium-binding EF-hand motif. Fourteen cysteine residues conserved among all the secreted forms of SPARCs were present in the Artemia SPARC, and four extra cysteine residues were also found in it. The extra residues were conserved among SPARCs of the arthropods and the nematode. Phylogenetic analyses showed that the sequences of SPARCs were grouped into those of vertebrates and invertebrates. Though the structural organization of SPARC was conserved among all the species studied, SPARC within a group was highly conserved within that group, but divergent between the two. Northern blots revealed the presence of a 1.1 kb mRNA, which was faintly expressed in embryos and considerably detected in prenauplii and nauplii. The isolation of a SPARC cDNA from Artemia franciscana provides intriguing features of the divergent protein, SPARC.

Amino Acid Motifs↗
PubMed2001

Human monocyte x mouse melanoma fusion hybrids express human gene.

Artificial fusion of human monocyte with Cloudman S91 mouse melanoma cells resulted in hybrids that showed increased motility in vitro, enhanced metastatic potential in vivo, and also tended to be super melanotic (Rachkovsky et al., Clin. Exp. Metastasis 16 (1998) 299). However, no gene derived from monocytes has been shown to be expressed in these hybrids until now. Similar observations have also been noted in hybrids originating from mouse macrophage and mouse melanoma cells. Having the advantage of species differences in mouse x human hybrids, we are able, this time, to show by RT-PCR that some genes specific to the human genome are expressed in these hybrids, indicating that not only is the genomic DNA from parental monocytes integrated in the hybrids but also some genes are being expressed. This observation may lead us to find contributory genes from monocyte and/or macrophage that are responsible for modulating the genotypes and hence the phenotypes in the hybrids.

Animals↗
PubMed2001

Expression of mRNA encoding extracellular matrix glycoproteins SPARC and SC1 is temporally and spatially regulated in the developing cochlea of the rat inner ear.

SPARC is a multifunctional extracellular matrix (ECM) glycoprotein that shares partial sequence homology with SC1/hevin. These ECM molecules exhibit calcium-binding properties and modulate cellular interactions. This study examines the expression of SC1 and SPARC mRNA in the developing cochlea of the rat inner ear prior to and after the onset of hearing. At all ages examined, SC1 mRNA is highly expressed in neurons of the spiral ganglion. In contrast, SPARC transcripts are not detected in the spiral ganglion but are enriched in the temporal bone and cartilaginous otic capsule surrounding the cochlea. Both SC1 and SPARC mRNA are expressed in connective tissue elements involved in maintaining ionic homeostasis of cochlear fluids. SC1 mRNA is localized to type III fibrocytes of the spiral ligament (slg) and marginal cells of the stria vascularis, while SPARC mRNA is apparent in the spiral limbus and type I fibrocytes of the slg. At postnatal day 10, SPARC mRNA shows a dramatic change in expression. High levels of SPARC transcripts are induced in Deiters cells (dc) of the organ of Corti. Interestingly, this induction of SPARC mRNA correlates with the onset of hearing. This suggests that SPARC may play a role in calcium regulation in dc when functional maturation of the cochlea is attained and rapid changes in calcium levels are required.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1989

Extracellular matrix in bone marrow cell cultures. Synthesis of a 45k non-collagenous protein and a 17k protein sensitive to bacterial collagenase.

Proteins produced by bone marrow constituents are of importance to hematopoiesis and osteogenesis. To elaborate the role of bone marrow in these functions the proteins synthesized by rat bone marrow cells in culture were evaluated. In addition to types I and III procollagen and fibronectin, two novel proteins were produced by the adherent stromal cells, a 45 kDa protein, and a 17 kDa protein which is sensitive to bacterial collagenase. The 45k protein is sensitive to pepsin digestion, contains no disulfide bonds, has no precursors or breakdown products on pulse-chase analysis and is maximally synthesized in young cultures (5 days old) with decreased synthesis as time in culture increases. The 17k protein is sensitive to digestion by bacterial collagenase and pepsin, appears without precursors or breakdown products on pulse-chase analysis and is maximally synthesized in 5 day old cultures. Synthesis decreases with longer times in culture. The 17k protein is not a degradation product of a collagen precursor and appears to be a novel protein in bone marrow cell cultures.

Animals↗
PubMed2000

SPARC, a matricellular protein: at the crossroads of cell-matrix.

SPARC is a multifunctional glycoprotein that belongs to the matricellular group of proteins. It modulates cellular interaction with the extracellular matrix (ECM) by its binding to structural matrix proteins, such as collagen and vitronectin, and by its abrogation of focal adhesions, features contributing to a counteradhesive effect on cells. SPARC inhibits cellular proliferation by an arrest of cells in the G1 phase of the cell cycle. It also regulates the activity of growth factors, such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF)-2, and vascular endothelial growth factor (VEGF). The expression of SPARC in adult animals is limited largely to remodeling tissue, such as bone, gut mucosa, and healing wounds, and it is prominent in tumors and in disorders associated with fibrosis. The crystal structure of two of the three domains of the protein has revealed a novel follistatin-like module and an extracellular calcium-binding (EC) module containing two EF-hand motifs. The follistatin-like module and the EC module are shared by at least four other proteins that comprise a family of SPARC-related genes. Targeted disruption of the SPARC locus in mice has shown that SPARC is important for lens transparency, as SPARC-null mice develop cataracts shortly after birth. SPARC is a prototypical matricellular protein that functions to regulate cell-matrix interactions and thereby influences many important physiological and pathological processes.

Animals↗
PubMed2001

SPARC, a matricellular protein: at the crossroads of cell-matrix communication.

SPARC is a multifunctional glycoprotein that belongs to the matricellular group of proteins. It modulates cellular interaction with the extracellular matrix (ECM) by its binding to structural matrix proteins, such as collagen and vitronectin, and by its abrogation of focal adhesions, features contributing to a counteradhesive effect on cells. SPARC inhibits cellular proliferation by an arrest of cells in the G1 phase of the cell cycle. It also regulates the activity of growth factors, such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF)-2, and vascular endothelial growth factor (VEGF). The expression of SPARC in adult animals is limited largely to remodeling tissue, such as bone, gut mucosa, and healing wounds, and it is prominent in tumors and in disorders associated with fibrosis. The crystal structure of two of the three domains of the protein has revealed a novel follistatin-like module and an extracellular calcium-binding (EC) module containing two EF-hand motifs. The follistatin-like module and the EC module are shared by at least four other proteins that comprise a family of SPARC-related genes. Targeted disruption of the SPARC locus in mice has shown that SPARC is important for lens transparency, as SPARC-null mice develop cataracts shortly after birth. SPARC is a prototypical matricellular protein that functions to regulate cell-matrix interactions and thereby influences many important physiological and pathological processes.

Animals↗
PubMed2002

Domain structure and organisation in extracellular matrix proteins.

Extracellular matrix (ECM) proteins are large modular molecules built up from a limited set of modules, or domains. The basic folds of many domains have now been determined by crystallography or NMR spectroscopy. Recent structures of domain pairs and larger tandem arrays, as well as of oligomerisation domains, have begun to reveal the principles underlying the higher order architecture of ECM proteins. Structural information, coupled with site-directed mutagenesis, has been instrumental in showing how adjacent domains can co-operate in ligand binding. Very recently, the first heterotypic ECM protein complexes have become available. Here, we review the advances of the last 5 years in understanding ECM protein structure, with special emphasis on those structures that have given insight into the biological functions of ECM proteins.

Activins↗
PubMed1996

Extracellular calcium-binding proteins.

Point mutations in Ca2+-binding sites of extracellular matrix proteins have been identified as the cause of human disorders such as Marfansyndrome and pseudoachondroplasia. Although the modes of Ca2+ binding and the effects of point mutations are not yet understood in these two cases, new insight was recently gained by X-ray and NMR structure determinations of several other extracellular proteins; these studies revealed a diversity of functions of Ca2+ ions. Ca2+ may induce a profound conformational change within a single domain, may bridge adjacent domains and thus direct the relative domain orientation and supramolecular structure, or may be involved in carbohydrate and membrane binding.

1-Carboxyglutamic Acid↗
PubMed1998

Importance of the basement membrane protein SPARC for viability and fertility in Caenorhabditis elegans.

The basement membrane is a specialized extracellular matrix located at epithelial-mesenchymal boundaries that supports cell adhesion, migration, and proliferation; it is highly conserved between invertebrates and vertebrates [1,2]. One of its component proteins, SPARC (osteonectin/BM-40), binds calcium and collagens, and can modulate cell-matrix interactions, so altering cell shape, growth, and differentiation [3,5]. The tissue distribution of a secreted fusion protein containing SPARC and green fluorescent protein (GFP) was analyzed in Caenorhabditis elegans. The protein localized to most basement membranes along body wall and sex muscles, and was also deposited around the pharynx and the gonad, in the spermatheca and at the distal tip cells. The contributions of SPARC to C. elegans development were determined using RNA interference, which accurately phenocopies loss-of-function defects [6-8]. A reduction in the amount of SPARC protein resulted in embryonic or larval lethality in a significant proportion of progeny. Those that survived developed a 'clear' phenotype characterized by a lack of gut granules, which made the animals appear transparent, plus small size, and sterility or reduced fecundity. No significant morphological abnormalities were observed, indicating that SPARC plays a regulatory rather than structural role in modulating cell-matrix interactions during normal development and reproduction.

Animals↗
PubMed2001

SPARC and the kidney glomerulus: matricellular proteins exhibit diverse functions under normal and pathological conditions.

In the last decade, numerous studies have emphasized the important functions that matricellular proteins subserve during angiogenesis, wound healing, and the maintenance of organ and tissue integrity. Matricellular proteins are defined as a group of secreted regulatory macromolecules that are not structural components of the extracellular matrix (ECM) but rather mediate interactions between the ECM and cells. One of these matricellular proteins, termed SPARC (secreted protein acidic and rich in cysteine), is produced during the process of wound healing and is prominent in several types of injury. An excessive deposition of glomerular matrix and an elevated proliferation of certain glomerular cells characterize a variety of kidney diseases. The proliferation of these cells is associated typically with the remodeling process that occurs after kidney injury, and is, at least in part, modulated by the altered expression of ECM, various growth factors, and the elevated production of matricellular proteins (e.g., SPARC). The secretion of one or more of the matricellular proteins can lead to expansion of the glomerular basement membrane, infiltration of immunocompetent cells, and, in some cases, to a reversal of the pathological condition. However, these proteins can also contribute collectively to renal fibrosis, glomerulosclerosis, glomerulonephritis, and the eventual loss of renal function. The purpose of this review is to evaluate the multiple functions of SPARC in the kidney glomerulus under normal and pathological conditions.

Animals↗
PubMed1999

SPARC (osteonectin/BM-40).

SPARC (Secreted ProteinAcidic and Rich in Cysteine) is a prototype of a family of biologically active glycoproteins that bind to cells and to extracellular matrix (ECM) components. It is expressed spatially and temporally during embryogenesis, tissue remodeling and repair. SPARC is a modular protein (34 kDa) comprised of three structural domains, one or more of which are implicated in the regulation of cell adhesion, proliferation, matrix synthesis/turnover. Rapid proteolysis of SPARC by extracellular proteases accounts for its transient detection in the extracellular environment. The proposed roles of SPARC in the development of cataracts and the regulation of angiogenesis during wound healing and tumor growth account for the recent attention it has received from the biomedical community.

Animals↗
PubMed2000

The role of basement membrane proteins on the expression of neural cell adhesion molecule (N-CAM) in an adenoid cystic carcinoma cell line.

We investigated the presence of neural cell adhesion molecule (N-CAM) in the adenoid cystic carcinoma cell line CAC2 using immunofluorescence microscopy. Additionally, we analysed the role of laminin and type IV collagen in N-CAM expression. We demonstrated that cultured adenoid cystic carcinoma cells express N-CAM. Control cells presented a scattered N-CAM expression on cell membrane, and type IV collagen had no effect in N-CAM distribution. CAC2 cells grown on laminin-coated coverslips expressed N-CAM concentrated on cell lamellipodia suggesting relationship with migratory activity. Our results showed that cultured adenoid cystic carcinoma cells express N-CAM and this expression is modulated by extracellular matrix.

Carcinoma, Adenoid Cystic↗
PubMed1996

Phase-Dependent effects of transforming growth factor beta 1 on osteoblastic markers of human osteoblastic cell line sV-HFO during mineralization.

A human osteoblastic cell line (SV-HFO) established in our laboratory expresses osteoblastic markers, including mineralization in vitro, in response to differentiation-inducing agents such as dexamethasone. In this study, we examined the effects of transforming growth factor beta 1 (TGF-beta 1) on the mineralization of SV-HFO cells and show that TGF-beta 1 inhibited the mineralization of the cells via down regulation of tetranectin and alkaline phosphatase without influencing other osteoblastic markers. To examine precisely the effects of TGF-beta 1 on the process of mineralization, we tentatively divided the whole process of mineralization into four phases: induced ALP activity (days 0-5), maximal ALP activity (days 5-10), early mineralization (days 10-15), and progressive mineralization (days 15-20). These inhibitory effects of TGF-beta 1 on the expression of tetranectin and alkaline phosphatase, like that on mineralization, were observed only when TGF-beta 1 was applied in the early phase of the process of mineralization. On the other hand, the other osteoblastic markers were not influenced by treatment with TGF-beta 1. These results suggest that TGF-beta 1 may inhibit mineralization of osteoblasts by the downregulation of tetranectin and alkaline phosphatase expression in the early phase. Thus, TGF-beta 1 has phase-dependent effects on a human osteoblastic cell line during the process of mineralization.

Alkaline Phosphatase↗
PubMed2005

Identifying the SPARC binding sites on collagen I and procollagen I by atomic force microscopy.

SPARC (secreted protein acidic and rich in cysteine) is a matricellular protein associated with the extracellular matrix (ECM). It has been found that the production of collagen I is a requisite for the association of SPARC with ECM, and studies with SPARC-null mice indicate that SPARC plays a role in modifying the structure of collagen fibers. It is not known, however, whether SPARC interacts with the collagen I precursor, procollagen I. In this study, the binding of SPARC to collagen I and procollagen I was verified by surface plasmon resonance. The SPARC-binding sites on collagen I and procollagen I were identified by directly visualizing their complexes using tapping-mode atomic force microscopy (TM-AFM). The characteristic chain end feature in collagen I is not readily detected by AFM, so unambiguous location of the binding sites relative to the C- or N-termini is difficult. In contrast, procollagen I, with its large globular C-propeptide, permits easy identification of the C-terminus. Histograms were constructed and compared based on the distances of the bound SPARC to the C-terminus of procollagen I and to the closest end of collagen I. There is a broad distribution of SPARC binding sites on procollagen I with the most preferred binding region located approximately 1/3 from the C-terminus. Characterization of the SPARC-binding sites on collagen I and procollagen I provides useful information for further understanding of the functional implications of their interactions.

Animals↗
PubMed2001

SPARC modulates cell growth, attachment and migration of U87 glioma cells on brain extracellular matrix proteins.

We have identified secreted protein acidic and rich in cysteine (SPARC) as a potential glioma invasion-promoting gene. To determine whether SPARC alters the growth, attachment, or migration of gliomas, we have used U87T2 and doxycycline-regulatable SPARC-transfected clones to examine the effects of SPARC on (1) cell growth, (2) cell cycle progression, (3) cell attachment, and (4) cell migration, using growth curves, flow cytometry, attachment, and migration analyses on different brain ECMs, including collagen IV, laminin, fibronectin, vitronectin, hyaluronic acid, and tenascin. Our data indicate that SPARC delays tumor cell growth in the log phase of the growth curve. The clones secreted different levels of SPARC. The clone secreting the lowest level of SPARC was associated with a higher percentage of cells in G2M, whereas the clones secreting the higher levels of SPARC were associated with a greater percentage of cells in G0/G1. In comparison to the parental U87T2 clone, the SPARC-transfected clones demonstrated increased attachment to collagen, laminin, hyaluronic acid, and tenascin, but not to vitronectin or fibronectin. SPARC-transfected clones also demonstrated altered migration on the different extracellular matrix proteins. The modulation of migration, either positive or negative, was associated with changes in the level of secreted SPARC. These data suggest that SPARC may modulate glioma proliferation and invasion by modulating both the growth and migration of glioma cells.

Brain Neoplasms↗
PubMed2002

Doxycycline-inducible expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells results in growth inhibition.

SPARC (secreted protein acidic and rich in cysteine)/BM40/Osteonectin is a matricellular protein with multiple effects on cell behaviour. In vitro, its major known functions are anti-adhesive and anti-proliferative, and it is associated with tissue remodelling and cancer in vivo. SPARC is overexpressed in many cancers, including breast cancer, and the effects of SPARC seem to be cell type-specific. To study the effects of SPARC on breast cancer, we transfected SPARC into the MDA-MB-231 BAG, human breast cancer cell line using the Tet-On inducible system. By western analysis, we found low background levels in the MDA-MB-231 BAG and clone X parental cells, and prominent induction of SPARC protein expression after doxycycline treatment in SPARC transfected clones X5, X21, X24 and X75. Induction of SPARC expression did not affect cell morphology or adhesiveness to collagens type I and IV, but it slowed the rate of proliferation in adherent cultures. Cell cycle analysis showed that SPARC slowed the progression to S phase. Doxycycline induction of SPARC also slowed the rate of monolayer wound closure in the cultured wound healing assay. Thymidine inhibition of proliferation abrogated this effect, confirming that it was due to anti-proliferation rather than inhibition of migration. Consistent with this, we were unable to detect any differences in migration and Matrigel outgrowth analysis of doxycycline-stimulated cells. We conclude that SPARC is inhibitory to human breast cancer cell proliferation, and does not stimulate migration, in contrast to its stimulatory effects reported for melanoma (proliferation and migration) and glioma (migration) cells. Similar growth repression by SPARC has been reported for ovarian cancer cells, and this may be a common feature among carcinomas.

Anti-Bacterial Agents↗
PubMed1998

SPARC/osteonectin mRNA is induced in blood vessels following injury to the adult rat cerebral cortex.

Recently we described the pattern of expression of the anti-adhesive glycoprotein SPARC/osteonectin in the developing and adult brain. SPARC mRNA was present in developing blood vessels during neurogenesis, but was not detected in the mature vasculature. We have now examined the effect of a lesion to the adult rat cerebral cortex on the expression of SPARC by in situ hybridization. SPARC mRNA was increased in the zone proximal to the wound at 3 to 10 days after cortical brain injury. During this period, SPARC was induced in mature blood vessels close to the lesion site and in blood vessels which develop following injury. These results suggest a role for SPARC in the process of angiogenesis following injury to the adult cerebral cortex.

Anatomy, Cross-Sectional↗