Table of Contents - *182120
External Links:
Genome
DNA
Protein
Gene Info
Variation
Animal Models
Cellular Pathways
| *182120 | ||||||||||||||||||||||||||||||||||||||||||||||||
| SECRETED PROTEIN, ACIDIC, CYSTEINE-RICH; SPARC | ||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||
| OSTEONECTIN; ON | ||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: SPARC | ||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 5q33.1 Genomic coordinates (GRCh37): 5:151,041,007 - 151,066,516 (from NCBI) | ||||||||||||||||||||||||||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||
| Secreted protein acidic and rich in cysteine/osteonectin/BM40, or SPARC, is a matrix-associated protein that elicits changes in cell shape, inhibits cell-cycle progression, and influences the synthesis of extracellular matrix (ECM) (Bradshaw et al., 2003). | ||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||||||||||||||
| Swaroop and Francke (1987) used a mouse cDNA probe (Mason et al., 1986) to isolate and sequence a full-length cDNA from a human placental cDNA library. The human sequence was found to be strongly homologous to mouse SPARC, but only in the coding region. SPARC is identical to osteonectin (from Latin verb nectere, to bind, bridge or link), a protein important to bone calcification which was identified by Termine et al. (1981). It is a 32,000-dalton, bone-specific phosphoprotein that binds selectively to hydroxyapatite and to collagen fibrils at distinct sites. Osteonectin accounts for the unique property of bone collagen to undergo calcification; type I collagen of bone is identical to that of skin and tendon (see 120150). In bone, it is present in a concentration of 2.3 micrograms per 10 micrograms of protein. It is present also in dentin but absent from all other tissues. By comparison of protein sequences as well as investigation of the genes, Findlay et al. (1988) concluded that osteonectin is highly conserved between species. Naylor et al. (1989) demonstrated RFLPs of the ON gene which should be useful as markers on chromosome 5 and for investigating the possible role of osteonectin in bone diseases. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||||||||||||||
| SPARC, which can be selectively expressed by the endothelium in response to certain types of injury, induces rounding in adherent endothelial cells in vitro. From the results of studies on the influence of SPARC on endothelial permeability, Goldblum et al. (1994) concluded that SPARC regulates endothelial barrier function through F-actin-dependent changes in cell shape, coincident with the appearance of intercellular gaps, that provide a paracellular pathway for extravasation of macromolecules. By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including SPARC, were functionally validated. Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||
| The mouse Sparc gene is located on chromosome 11 (Mason et al., 1986). By Southern analysis of somatic cell hybrid DNA, Swaroop and Francke (1987) assigned the human SPARC gene to chromosome 5 and found RFLPs for the same. Swaroop et al. (1988) narrowed the assignment to 5q31-q33 by in situ chromosomal hybridization. By fluorescence in situ hybridization, Le Beau et al. (1993) mapped the SPARC gene to 5q31.3-q32. | ||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||
| Gilmour et al. (1998) generated Sparc-deficient mice by targeted disruption. The mice appeared normal and fertile until around 6 months of age, when they developed severe eye pathology characterized by cataract formation and rupture of the lens capsule. The first sign of lens pathology occurred in the equatorial bow region where vacuoles gradually formed within differentiating epithelial cells and fiber cells. The lens capsule, however, showed no qualitative changes in the major basal lamina proteins laminin, collagen IV, perlecan, or entactin. The absence of Sparc in mice gives rise to aberrations in the structure and composition of the extracellular matrix that result in generation of cataracts, development of severe osteopenia, and accelerated closure of dermal wounds. Bradshaw et al. (2003) showed that Sparc-null mice have greater deposits of subcutaneous fat and larger epididymal fat pads in comparison with wildtype mice. Similar to earlier studies of SPARC-null dermis, they observed a reduction in collagen I in Sparc-null fat pads in comparison with wildtype. Although elevated levels of serum leptin were observed in Sparc-null mice, their overall body weights were not significantly different from those of wildtype counterparts. The diameters of adipocytes in epididymal fat pads from Sparc-null versus wildtype mice were 252 +/- 61 and 161 +/- 33 microM, respectively, and there was an increase in adipocyte number within the Sparc-null fat pads in comparison with wildtype pads. Thus, the absence of Sparc appeared to result in an increase in the size of individual adipocytes as well as an increase in the number of adipocytes per fat pad. In fat pads isolated from wildtype mice, Sparc mRNA was associated with both the stromal/vascular and adipocyte fractions. Bradshaw et al. (2003) proposed that Sparc limits the accumulation of adipose tissue in mice in part through its demonstrated effects on the regulation of cell shape and production of the extracellular matrix. Brekken et al. (2003) reported that implanted tumors grew more rapidly in Sparc-null mice than in wildtype mice and showed alterations in the production and organization of ECM components and a decrease in the infiltration of macrophages. There was no difference in the levels of angiogenic growth factors, although there was a statistically significant decrease in total vascular area in tumors grown in Sparc-null mice. Brekken et al. (2003) concluded that endogenous SPARC is important for the appropriate organization of the ECM in response to implanted tumors and that the ECM has a crucial role in regulating tumor growth. In laser-injury studies in mice, Nozaki et al. (2006) observed that injury-induced choroidal neovascularization (CNV) was increased by excess Vegf (192240) before injury but was suppressed by Vegf after injury. This effect was mediated via Vegfr1 (FLT1; 165070) activation and Vegfr2 (KDR; 191306) deactivation: excess Vegf increased CNV before injury because Vegfr1 activation was silenced by Sparc, and a transient decline in Sparc after injury created a temporal window in which Vegf signaling was routed primarily through Vegfr1. | ||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||
| Mason et al. (1986); Schwartz et al. (1988); Stenner et al. (1986) | ||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||