QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 12, 5446-5455, December 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-03-0289v1 19/12/5446    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Fujita, T. Articles by Wan, Y. Search for Related Content PubMed PubMed Citation Articles by Fujita, T. Articles by Wan, Y.

Regulation of the Anaphase-promoting Complex–Separase Cascade by Transforming Growth Factor-β Modulates Mitotic Progression in Bone Marrow Stromal Cells

Takeo Fujita^*,, Michael W. Epperly, Hui Zou, Joel S. Greenberger, and Yong Wan^*

*Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261; Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and Department of Cancer and Thoracic Surgery, Okayama University School of Medicine, Okayama 700-8558, Japan

Submitted March 17, 2008; Revised September 19, 2008; Accepted September 30, 2008
Monitoring Editor: Jonathan Chernoff

Alteration of the tumor microenvironment by aberrant stromal cells influences many aspects of cell biology, including differentiation of stem cells and tumor metastasis. The role of transforming growth factor (TGF)-β signaling in stromal cells of the tissue microenvironment is critical to both pathways. We examined murine marrow stromal cells with deletion of Smad3 and found that they have an altered cell cycle profile, with a higher fraction of cells in G2/M phase. Deletion of Smad3 significantly abrogates TGF-β signaling and suppresses phosphorylation of CDC27–anaphase-promoting complex (APC) during mitosis, thereby resulting in elevated cyclin-dependent kinase (CDK)1 activity via increased levels of cyclin B. Enhanced CDK1 activity due to deregulation of APC leads in turn to hyperphosphorylation of separase, impeding chromatid separation. A residue Ser1126Ala mutation in separase specifically abolished separase hyperphosphorylation in Smad3-deficient cells. The present results unveil a new function for the TGF-β pathway in the regulation of APC to mediate chromatid separation during mitosis.

Address correspondence to: Yong Wan (yow4{at}pitt.edu).