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Published on: August 27, 2013

SPARC inhibits epithelial cell proliferation in part through stimulation of the transforming growth

Barbara J Schiemann1, Jason R Neil, William P Schiemann

  • 1Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. schiemannwp@njc.org

Molecular Biology of the Cell
|October 1, 2003
PubMed

Insights

Secreted protein acidic rich in cysteine (SPARC) inhibits epithelial cell proliferation by hijacking the transforming growth factor-beta (TGF-β) pathway. SPARC’s extracellular domain mediates this effect via Smad2/3 signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Secreted protein acidic rich in cysteine (SPARC) is a multifunctional protein involved in cell interactions.
  • SPARC's role in regulating epithelial cell growth is not well understood.
  • SPARC influences cell adhesion, motility, and proliferation.

Purpose of the Study:

  • To investigate the mechanism by which SPARC regulates epithelial cell proliferation.
  • To determine if SPARC utilizes the transforming growth factor-beta (TGF-β) signaling pathway.
  • To identify the specific domain of SPARC responsible for inhibiting cell growth.

Main Methods:

  • Utilized TGF-β-sensitive (Mv1Lu) and insensitive (R1B) cell lines.
  • Overexpressed dominant-negative Smad3 to assess TGF-β pathway involvement.
  • Investigated the role of the SPARC extracellular calcium-binding domain (SPARC-EC).
  • Measured Smad2/3 phosphorylation and nuclear translocation.
  • Assessed TGF-β-responsive reporter gene expression.

Main Results:

  • SPARC significantly inhibited DNA synthesis in Mv1Lu cells but moderately in R1B cells.
  • Dominant-negative Smad3 attenuated SPARC-induced growth arrest.
  • SPARC-EC inhibited Mv1Lu cell proliferation, but not R1B cells.
  • SPARC and SPARC-EC stimulated Smad2 phosphorylation and nuclear translocation in a TGF-β-dependent manner.
  • SPARC did not affect BMP-regulated Smad1 phosphorylation.
  • SPARC activated TGF-β-responsive reporter gene expression via a TGF-β receptor and Smad2/3 pathway.

Conclusions:

  • SPARC inhibits epithelial cell proliferation through a novel mechanism involving the TGF-β signaling pathway.
  • The extracellular domain of SPARC is crucial for this inhibitory effect.
  • SPARC selectively commandeers the TGF-β receptor and Smad2/3 pathway to regulate cell growth.

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