Understanding neurogenesis is contingent upon elucidating cell cycle exit. An essential feature of all cell cycle transitions is their irreversibility. Once a commitment to enter a particular cell cycle phase is made, return to the previous phase is not possible. This is in part due to ubiquitin mediated proteolysis pathways that target substrates for proteasomal degradation. Ubiquitin mediated proteolysis pathways contain E1, E2, and E3 enzymes that regulate both the timing and fidelity of degradation events. One of the most important E3 enzymes is a multi-subunit complex named the Anaphase Promoting Complex, or APC. The APC controls both the metaphase to anaphase transition and mitotic exit. The APC is also active during cell cycle exit and differentiation of neuronal precursors. The APC degrades the ubiquitin ligase component Skp2, which allows p27kip1 levels to rise, thereby inducing cell cycle exit. The overall goal of this research is to test the hypothesis that ubiquitin mediated proteolysis controlled by the ubiquitin ligase the Anaphase Promoting Complex (APC) is required for cell cycle exit in the developing nervous system.

Public Health Relevance

We are studying the mechanisms controlling neuronal precursor cell proliferation. These mechanisms are often misregulated in neurological diseases and cancers. Our work will identify both targets and small molecule inhibitors of cell cycle transitions, which can be used for both academic clinical researches to treat diseases such as medulloblastoma.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Owens, David F
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Scripps Research Institute
La Jolla
United States
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Penas, Clara; Govek, Eve-Ellen; Fang, Yin et al. (2015) Casein kinase 1? is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis. Cell Rep 11:249-60
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Pastori, Chiara; Kapranov, Philipp; Penas, Clara et al. (2015) The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation. Proc Natl Acad Sci U S A 112:8326-31
Trojanowsky, Michelle; Vidovic, Dusica; Simanski, Scott et al. (2015) Screening of cell cycle fusion proteins to identify kinase signaling networks. Cell Cycle 14:1274-81
Penas, Clara; Mishra, Jitendra K; Wood, Spencer D et al. (2015) GSK3 inhibitors stabilize Wee1 and reduce cerebellar granule cell progenitor proliferation. Cell Cycle 14:417-24
Allen, Bryce K; Mehta, Saurabh; Ember, Stewart W J et al. (2015) Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4. Sci Rep 5:16924
Penas, Clara; Hatten, Mary E; Ayad, Nagi G (2015) The APC/C and CK1 in the developing brain. Oncotarget 6:16792-3
Long, Jun; Li, Bin; Rodriguez-Blanco, Jezabel et al. (2014) The BET bromodomain inhibitor I-BET151 acts downstream of smoothened protein to abrogate the growth of hedgehog protein-driven cancers. J Biol Chem 289:35494-502
Stathias, Vasileios; Pastori, Chiara; Griffin, Tess Z et al. (2014) Identifying glioblastoma gene networks based on hypergeometric test analysis. PLoS One 9:e115842
Plotkin, Amy; Volmar, Claude-Henry; Wahlestedt, Claes et al. (2014) Transcriptional repression of ER through hMAPK dependent histone deacetylation by class I HDACs. Breast Cancer Res Treat 147:249-63

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