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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067289-06
Application #
8658857
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2010-09-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$425,432
Indirect Cost
$83,702
Name
University of Miami School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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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
Clarke, Jennifer; Penas, Clara; Pastori, Chiara et al. (2013) Epigenetic pathways and glioblastoma treatment. Epigenetics 8:785-95