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Regulation of the anaphase-promoting complex-separase cascade by transforming growth factor-beta modulates mitotic

Takeo Fujita1, Michael W Epperly, Hui Zou

  • 1Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261, USA.

Molecular Biology of the Cell
|October 10, 2008
PubMed

Insights

Transforming growth factor-beta (TGF-β) signaling, regulated by Smad3, controls cell division. Smad3 deficiency disrupts mitosis by impairing the anaphase-promoting complex (APC), leading to errors in chromatid separation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Biology

Background:

  • Aberrant stromal cells in the tumor microenvironment impact stem cell differentiation and metastasis.
  • Transforming growth factor-beta (TGF-β) signaling in stromal cells is crucial for these processes.

Purpose of the Study:

  • To investigate the role of Smad3, a key mediator of TGF-β signaling, in regulating cell cycle progression and mitosis in murine marrow stromal cells.
  • To elucidate the molecular mechanisms by which Smad3 deficiency affects mitosis and chromatid separation.

Main Methods:

  • Deletion of Smad3 in murine marrow stromal cells.
  • Analysis of cell cycle profiles.
  • Assessment of TGF-β signaling, including CDC27-anaphase-promoting complex (APC) phosphorylation.
  • Measurement of cyclin-dependent kinase (CDK)1 activity and cyclin B levels.
  • Investigation of separase phosphorylation using a Ser1126Ala mutation.

Main Results:

  • Smad3-deficient cells exhibited an altered cell cycle profile with an increased proportion in the G2/M phase.
  • Deletion of Smad3 abrogated TGF-β signaling and suppressed CDC27-APC phosphorylation during mitosis.
  • This led to elevated CDK1 activity due to increased cyclin B levels and APC deregulation.
  • Hyperphosphorylation of separase occurred, impeding chromatid separation, which was specifically abolished by the Ser1126Ala mutation in separase.

Conclusions:

  • The TGF-β/Smad3 pathway plays a novel role in regulating the anaphase-promoting complex (APC) during mitosis.
  • Dysregulation of APC due to Smad3 deficiency leads to impaired chromatid separation.
  • These findings reveal a new mechanism by which stromal cells influence cell division and potentially tumor progression.

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