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Regulation of SCFSKP2 Ubiquitin E3 Ligase Assembly and p27KIP1 Proteolysis by the PTEN Pathway and Cyclin D1
Jennifer Harrell Jonason, Nadia Gavrilova, Min Wu, Hui Zhang and Hong Sun
volume 6 | issue 8
15 April 2007Pages: 951 - 961
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The PTEN tumor suppressor functions as a phosphatase of phosphatidylinositol 3,4,5-trisphosphate (PIP3) and negatively regulates the PI 3-kinase signaling pathway. Our previous studies showed that PTEN expression causes accumulation of cyclin-dependent kinase inhibitor p27Kip1 and G1 cell cycle arrest. Here, we show that PTEN negatively regulates expression of cyclin D1 and that cyclin D1 plays a unique role in p27 proteolysis. Co-expression of cyclin D1, but not cyclin E, is sufficient to restore p27 levels in PTEN-expressing cells. Conversely, loss of cyclin D1 by siRNA causes p27 accumulation. Silencing of the cyclin D1 gene or inhibition of the PI 3-kinase pathway prevents formation of the SCFSKP2 complex, with a simultaneous increase in CUL1 binding to CAND1. CAND1-CUL1 binding is known to block the accessibility of CUL1 to SKP1 and SKP2. We have found that CUL1 is less neddylated in cells that have lost cyclin D1 expression. Using an in vitro extract system, we found that the extracts prepared from cells lacking cyclin D1 have reduced activity to neddylate CUL1, in a manner similar to extracts from cells treated with a PI 3-kinase inhibitor or in G0 resting cells. Consistenly, the steady state levels of CUL1 neddylation were found lower under these conditions. Our studies reveal that PTEN/PI 3-kinase signaling and cyclin D1 control a novel pathway that regulates assembly of the SCFSKP2 complex by modulating cullin neddylation and CAND1 binding at the G1/S cell cycle transition.
Authors
Jennifer Harrell Jonason
Yale University School of Medicine, New Haven, Connecticut
Nadia Gavrilova
Yale University School of Medicine, New Haven, Connecticut
Min Wu
University of Michigan, Ann Arbor, MI
Hui Zhang
University of Michigan, Ann Arbor, MI
Hong Sun
Yale University School of Medicine, New Haven, Connecticut
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.