A number of cDNAs (SC1, QR1, and hevin) have been shown to be similar to SPARC (secreted protein acidic and rich in cysteine), a matricellular protein that regulates cell adhesion, cell cycle, and matrix assembly and remodeling. These proteins are 61-65% identical in the final 200 residues of their C-termini; their N-terminal sequences are related but more divergent. All have an overall acidic pl, with a follistatin-like region that is rich in cysteine, and a Ca+2 binding consensus sequence at the C-terminus. Using degenerate primers representing the most highly conserved region in SPARC, SC1, and QR1, we identified a 300-BP SC1 clone in a primary polymerase chain reaction (PCR) screen of a mouse brain cDNA library. This cDNA was used to obtain a full-length clone, which hybridized to a 2.8-KB RNA abundant in brain. Mouse SC1 displays a similarity of 70% to mouse SPARC at the amino acid level. Northern blot and RNAse protection assays revealed a 2.8-KB mRNA expressed at moderate levels (relative to brain) in mouse heart, adrenal gland, epididymis, and lung, and at low levels in kidney, eye, liver, spleen, submandibular gland, and testis. In contrast to SPARC, in situ hybridization showed expression of SC1 mRNA in the tunica media and/or adventitia of medium and large vessels; transcripts were not detected in capillaries, venules, or large lymphatics. The distribution of transcripts for SC1 was also different from that of SPARC in several organs, including adrenal gland, lung, heart, liver, and spleen. Moreover, SC1 mRNA was not evident in endothelium cultured from rat heart, bovine fetal and adult aorta, mouse aorta, human omentum, and bovine retina. Cultured smooth muscle cells and fibroblasts also failed to express SC1 mRNA. The absence of SC1 transcript in cultured cells indicates that the SC1 gene is potentially sensitive to regulatory factors in serum or to a three-dimensional architecture conferred by the extracellular matrix that is lacking in vitro. In conclusion, the expression of SPARC and SC1 appears to be coincident in specific tissues (e.g., adrenal gland and brain), but these proteins exhibit distinct expression patterns in most organs of the mouse. Because SC1 and SPARC are structurally similar and exhibit counteradhesive effects on cultured cells, their overlapping and/or adjacent expression in most tissues predicts that one protein might compensate functionally, at least in part, for the other.