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.
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.
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|Penas, Clara; Govek, Eve-Ellen; Fang, Yin et al. (2015) Casein kinase 1Î´ is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis. Cell Rep 11:249-60|
|Allen, Bryce K; Stathias, Vasileios; Maloof, Marie E et al. (2015) Epigenetic pathways and glioblastoma treatment: insights from signaling cascades. J Cell Biochem 116:351-63|
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|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|
|Penas, Clara; Hatten, Mary E; Ayad, Nagi G (2015) The APC/C and CK1 in the developing brain. Oncotarget 6:16792-3|
|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|
|Pastori, Chiara; Daniel, Mark; Penas, Clara et al. (2014) BET bromodomain proteins are required for glioblastoma cell proliferation. Epigenetics 9:611-20|
|Penas, Clara; Ramachandran, Vimal; Simanski, Scott et al. (2014) Casein kinase 1Î´-dependent Wee1 protein degradation. J Biol Chem 289:18893-903|
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