Our overall research interests are in understanding how mammalian cells activate the programmed cell death pathway and die by apoptosis. Cell death by apoptosis occurs extensively during development and is seen in many pathological conditions such as after stroke and neurodegenerative. In contrast, the inability of cells to undergo apoptosis is a fundamental hallmark of cancers. Therefore, understanding the mechanism by which apoptosis is regulated in cells is clinically important and has significant translational potential.
We are particularly interested in identifying differences in the apoptotic pathway in postmitotic versus mitotic cells. An increased restriction of apoptosis is arguably beneficial for the long-term survival of postmitotic cells such as neurons that have limited regenerative potential and perform critical functions. Thus, we have focused our work on examining this pathway in neurons. Additionally, we are also studying apoptosis in embryonic stem (ES) cells, cancer cells, and in mouse models of neurodegeneration and brain tumors.
Key Neuronal Highlights:
- Cytochrome c-mediated caspase activation pathway is tightly regulated in neurons by multiple mechanisms.
- Dynamic changes (e.g. chromatic remodeling, miR-29 induction) highly restrict the apoptotic pathway with neuronal maturation.
- A distinct pathway can selectively induce the degeneration of neuronal axons while maintaining soma survival.
Cusack, C.L., V. Swahari, W.H. Henley, J.M. Ramsey, and M. Deshmukh. 2013. Distinct Pathways Mediate Axon Degeneration during Apoptosis and Axon-Specific Pruning. Nature Commun. 4: 1876. PMID: 23695670
Gershon, T.R., A.J. Crowther, I. Garcia, R. Annis, H. Yuan, C.R. Miller, A. Tikunov, J. Macdonald, J. Olson, and M. Deshmukh. 2013. Hexokinase-2 mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab. 1:2. Paper
Dumitru, R., V. Gama, B.M. Fagan, J. J. Bower, L.H. Pevny and M. Deshmukh. 2012. Human Embryonic Stem Cells have Constitutively Active Bax at the Golgi and are Primed to Undergo Rapid Apoptosis. Molecular Cell. 46:573-583. PMID: 22560721
Kole, A.J, V. Swahari, S.M. Hammond, and M. Deshmukh. 2011. miR-29b is Activated During Neuronal Maturation and Targets BH3-only Genes to Restrict Apoptosis. Genes Dev., 25:125-130. PMID: 21245165
Vaughn, A.E and M. Deshmukh. 2008. Glucose Metabolism Inhibits Apoptosis in Neurons and Cancer Cells by Redox Inactivation of Cytochrome c. Nature Cell Biol.. 10:1477-1483. PMID: 19029908
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