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MBC in Press, published online ahead of print June 27, 2003
Mol. Biol. Cell 10.1091/mbc.E03-01-0001

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Submitted on January 10, 2003
Revised on May 30, 2003
Accepted on May 31, 2003

SPARC Inhibits Epithelial Cell Proliferation in Part Through Stimulation of the TGF-{beta}-Signaling System

Barbara J. Schiemann1, Jason R. Neil2, and William P. Schiemann1*

1 Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Goodman Building, K1011, 1400 Jackson Street, Denver, Colorado 80206
2 Department of Pharmacology, University of Colorado Health Sciences Center, Denver, 4200 E. Ninth Ave, Denver, CO, 80262

* Corresponding author. E-mail address: schiemannwp{at}njc.org.

SPARC (Secreted Protein, Acidic and Rich in Cysteine) is a multifunctional secreted protein that regulates cell-cell and cell-matrix interactions, leading to alterations in cell adhesion, motility, and proliferation. Although SPARC is expressed in epithelial cells, its ability to regulate epithelial cell growth remains largely unknown. We show here that SPARC strongly inhibited DNA synthesis in TGF-{beta}-sensitive Mv1Lu cells, while moderately inhibiting that in TGF-{beta}-insensitive Mv1Lu cells (i.e., R1B cells). Overexpression of dominant-negative Smad3 in Mv1Lu cells, which abrogated growth arrest by TGF-{beta}, also attenuated growth arrest stimulated by SPARC. Moreover, the extracellular calcium-binding domain of SPARC (i.e., SPARC-EC) was sufficient to inhibit Mv1Lu cell proliferation, but not that of R1B cells. Similar to TGF-{beta} and Thrombospondin-1, treatment of Mv1Lu cells with SPARC or SPARC-EC stimulated Smad2 phosphorylation and Smad2/3 nuclear translocation: the latter response to all agonists was abrogated in R1B cells or by pretreatment of Mv1Lu cells with neutralizing TGF-{beta} antibodies. SPARC also stimulated Smad2 phosphorylation in MB114 endothelial cells, but had no effect on BMP-regulated Smad1 phosphorylation in either Mv1Lu or MB114 cells. Finally, SPARC and SPARC-EC stimulated TGF-{beta}-responsive reporter gene expression through a TGF-{beta} receptor- and Smad2/3-dependent pathway in Mv1Lu cells. Collectively, our findings identify a novel mechanism whereby SPARC inhibits epithelial cell proliferation by selectively commandeering the TGF-{beta} signaling system, doing so through coupling of SPARC-EC to a TGF-{beta} receptor- and Smad2/3-dependent pathway.




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