- B.S., St. Xavier's College, 1986
- Ph.D., Carnegie Mellon University, 1994
- Postdoc, Washington University, 1994-2000
- Joined the Neuroscience Center and the Department in 2000
- Burroughs Wellcome Fund
- National Institutes of Health
- American Heart Association
We are interested in exploring how cells regulate their survival and death. How does a cell decide whether to survive and cope, or trigger apoptosis in response to different stimuli? If the apoptotic pathway is activated, what is its mechanism and how is it regulated?
Cell death by apoptosis occurs extensively during development and is seen in many pathological conditions such as after stroke, neurodegenerative or cardiovascular diseases. In contrast, the inability of cells to undergo apoptosis is a fundamental hallmark of cancers. Therefore, understanding the mechanisms by which different cells regulate apoptosis has significant therapeutic implications.
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 that have limited regenerative potential and perform critical functions. Thus, we are examining these questions in a variety of cells including cancer cells, as well as postmitotic cells such as neurons, cardiomyocytes, myotubes, and mitotic fibroblasts. Recently, we have also started examining apoptosis regulation in embryonic stem cells.
- We have found that the cytochrome c-mediated caspase activation pathway is tightly regulated in neurons, cardiomyocytes and myotubes, but not in fibroblasts, by the caspase inhibitory protein XIAP.
- We have identified dynamic changes involving chromatin restriction at the Apaf-1 promoter occurring with neuronal maturation to even further restrict the apoptotic pathway in mature neurons.
- We have discovered a novel mechanism utilized by neurons and cancer cells involving glucose metabolism via the pentose phosphate pathway that inhibits apoptosis by directly inactivating cytochrome c.
Some Questions Currently Under Investigation
- Does XIAP deficiency make neurons more vulnerable to neurodegeneration?
- Are there fundamental differences in the regulation of the apoptotic pathway in mitotic versus postmitotic cells?
- Can we identify microRNAs that regulate apoptosis in mammalian cells?
- Are there common mechanisms of apoptosis regulation between neurons and cancer cells?
- How is apoptosis regulated in embryonic stem cells?
If interested in postdoctoral training in the lab, please send email to: email@example.com.
- Smith, M.I, YY. Huang, and M. Deshmukh. 2009. Skeletal Muscle Differentiation Evokes Endogenous XIAP to Restrict the Apoptotic Pathway. PLoS One. 4: e5097. (pdf)
- Vaughn, A.E and M. Deshmukh. 2008. Glucose Metabolism Inhibits Apoptosis in neurons and Cancer Cells by Redox Inactivation of Cytochrome c. Nat. Cell Biol. 10:1477-1483. (pdf)
- Johnson, C.E.,Y.Y. Huang, A.B. Parrish, M.I. Smith, A.E. Vaughn, K.M. Wright, Q. Zhang, T.V. Dyke, R.J. Wechsler-Reya, S. Kornbluth, and M. Deshmukh. 2007. Differential Apaf-1 Levels Allow Cytochrome c to Induce Apoptosis in Brain Tumors but not in Normal Neural Tissues. Proc. Natl. Acad. Sci. 104:20820-20825. (pdf) (Featured News Section).
- Wright, K.M., M.I. Smith, L. Farrag, and M. Deshmukh. 2007. Chromatin Modification of Apaf-1 Restricts the Apoptotic Pathway in Mature Neurons. J. Cell Biol. 179:825-832. (pdf) (Featured News Section) (Podcast - Biobytes)
- Smith, M.I. and M. Deshmukh. 2007. ER Stress Induced Apoptosis Requires Bax for Commitment and Apaf-1 for Execution in Primary Neurons. Cell Death & Differ. 14: 1011-1019. (pdf)
- Vaughn, A.E. and M. Deshmukh. 2007. Essential Postmitochondrial Function of p53 Uncovered in DNA Damage-Induced Apoptosis in Neurons. Cell Death & Differ. 14: 973-981. (pdf)
- Wright, K.M., A.E. Vaughn, and M. Deshmukh. 2007. Apoptosome dependent caspase-3 activation pathway is non-redundant and necessary for apoptosis in sympathetic neurons. Cell Death & Differ. 14: 625-633. (pdf)
- Wright, K.M. and M. Deshmukh. 2006. Restricting apoptosis for postmitotic cell survival and its relevance to cancer. Cell Cycle. 5: 1616-1620. (pdf)
- Potts, M.B., A.E. Vaughn, H. McDonough, C. Patterson, and M. Deshmukh. 2005. Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. J. Cell Biol. 171:925-930. (pdf)
- Wright, K.M., M.W. Linhoff, P.R. Potts, and M. Deshmukh. 2004. Decreased apoptosome activity with neuronal differentiation sets the threshold for strict IAP regulation of apoptosis. J. Cell Biol. 167:303-313. (pdf) (Featured Comments)
- Potts, P.R., S. Singh, M. Knezek, C.B. Thompson, and M. Deshmukh. (2003). Critical function of endogenous XIAP in regulating caspase activation during sympathetic neuronal apoptosis. J. Cell Biol. 163: 789-799. (pdf) (Featured Comments)
- Deshmukh, M., C. Du, X. Wang, and E.M. Johnson, Jr. (2002). Exogenous Smac induces competence and permits caspase activation in sympathetic neurons. J. Neurosci. 22: 8018-8027. (pdf)
- Deshmukh, M., K. Kuida, and E.M. Johnson, Jr. (2000). Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J. Cell Biol. 150: 131–143. (pdf)
- Deshmukh, M. and E.M. Johnson, Jr. (1998). Evidence for a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron. 21: 695–705. (pdf) (Featured comments)
- Holtzman, D.M. and M. Deshmukh. (1997). Caspases: A treatment target for neurodegenerative disease? Nature Med. 3: 954–955.