We study the mechanisms of ubiquitin-mediated cell cycle control and the deregulation of these processes in cancer. We are focused on the Anaphase Promoting Complex (APC), an essential E3 ligase, and master regulator of the cell cycle. The APC exists in two forms APCCdc20 and APCCdh1. Deregulated APC activity is common in tumors from several tissues, including breast, brain and colon. Yet, mutations in APC components are infrequent, indicating that abnormal APC control drives APC deregulation in cancer. Using proteomics, biochemical and biological assays, we are delineating the mechanisms controlling APC function to enhance our understanding of tumor biology and promote improved therapeutic strategies.
We have previously defined regulation of APCCdh1, a tumor suppressor, by the pseudosubstrate Emi1 and Cyclin E-Cdk2. Recently, we identified the deubiquitinating enzyme USP37 as an antagonist of APCCdh1 that promotes DNA synthesis. Our studies indicate that tight control of USP37 by APCCdh1 and the SCFβTrCP ligase is required for cell cycle progression. How USP37 may contribute to the diminished APCCdh1 function in cancer is a key focus of our research. In contrast to APCCdh1, inhibition of APCCdc20 is central to the efficacy of several anti-mitotic chemotherapeutics (e.g. Taxol). Inhibition of APCCdc20 is mediated by the spindle assembly checkpoint (SAC). We are dissecting mechanisms that antagonize and silence the SAC in an effort to identify potential biomarkers for predicting sensitivity to anti-mitotics. Defining these mechanisms may identify novel therapeutic targets as well.
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Summers MK, et al. The Chfr mitotic checkpoint protein arrests cells in early prophase with partially depolymerized lamins and cytoplasmic Cyclin B1. Oncogene, 2005 Apr 14;24(16):2589-98
Miller JJ, et al. Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev. 2006 Sep 1;20(17):2410-20
Summers MK, et al. The unique N terminus of the UbcH10 E2 enzyme controls the threshold for APC activation and enhances checkpoint regulation of the APC. Mol Cell. 2008 Aug 22;31(4):544-56.
Huang X, et al. Deubiquitinase USP37 is activated by CDK2 to antagonize APCCDH1 and promote S-phase entry. Mol.Cell, 2011 May 20;42(4):511-523
Torres JZ, et al. The STARD9/Kif16a Kinesin Associates with Mitotic Microtubules and Regulates Spindle Pole Assembly, Cell, 2011
Burrows AC, et al. Skp1-Cul1-F-box Ubiquitin Ligase (SCFβTrCP)-Mediated Destruction of the Ubiquitin-Specific Protease USP37 During G2-Phase Promotes Mitotic Entry. J. Biol. Chem. 2012 Oct 1.