Ameeta Kelekar, Ph.D.
MMC 609 Mayo
Minneapolis, MN 55455
Mechanisms of Apoptosis
Apoptosis is a tightly regulated biological process important for normal development, for the regulation of cell numbers and for the removal of aging or damaged cells in higher organisms, and aberrant regulation of the process can be the underlying cause of cancer. In order to develop reliable strategies to combat cancer, it is important to thoroughly understand the mechanisms underlying apoptosis in normal cells and to ask how and why these are dysregulated in malignant cells. The laboratory has two major areas of focus:
- Mechanisms underlying the activation of pro-apoptotic BH3 domain-containing members of the Bcl-2 family and the role of interactions between members of the Bcl-2 family, in promoting, accelerating or inhibiting apoptosis. The Bcl-2 family of apoptotic regulators comprises proteins that are both potent inhibitors of PCD as well as those that are potent promoters of death. Mitochondria are the sites of action of Bcl-2 family proteins. Pro-apoptotic members of the family promote the release of mitochondrial cytochrome c and cause cell death, while anti-apoptotic proteins prevent its release allowing cells to survive. A subset of pro-apoptotic Bcl-2 family members, referred to as the BH3-only proteins, is activated in response to specific apoptotic stimuli. These activated proteins interact with other Bcl-2 proteins at mitochondrial sites to promote death. Our efforts are directed, in part, towards identifying BH3 domain proteins that are activated in response to specific apoptotic stimuli and, in part, towards determining the mechanism of action of the activated proteins at mitochondrial sites.
- Alternative pathways of apoptotic caspase cascade amplification and their regulation. Activation of the cascade via initiator caspase, caspase-9, has been shown to be dependent on the release of mitochondrial cytochrome c into the cytosol. Our observations indicated that caspase-9 could be activated by at least one alternative mechanism that is independent of cytochrome c release. Recent data suggest that caspase-8, another initiator caspase, when activated following occupation and trimerization of the tumor necrosis factor (TNF) receptor, processes and activates caspase-9 in the absence of cytochrome c. Our studies also indicate that modification of murine procaspase-9 by CK2 (formerly casein kinase 2) in the vicinity of its primary processing motif promotes survival by protecting the protease from mistimed or inappropriate cleavage and activation.
- Bangalore University, Bangalore, India, BS (Chemistry, Botany, Zoology), 1976
- Bombay University, Bombay, India, MSc (Biochemistry), 1978
- Princeton University, Princeton, New Jersey, MS (Molecular Biology), 1985
- Princeton University, Princeton, New Jersey, PhD (Molecular Biology), 1987
- Duke University Medical Center, Durham, NC, Post Doctorate (Microbiology/Immunology), 1987-92
- Sanchez, C., P. Perfornis, A. Oskowitz, A. Boonjindasup, D. Cai. S. Dhule. B. Rowan, A. Kelekar, D. Krause, and R. Pochampally. Activation of autophagy in mesenchymal stem cells provides tumor stromal support. Carcinogenesis. 2011 Jul;32(7):964-72. doi: 10.1093/carcin/bgr029.
- Lowman X. H., M. A. McDonnell, O. A. Odumade, A. Kosloske, C. Jenness, C. B. Karim, R. Jemmerson, and A. Kelekar . The Proapoptotic Function of Noxa in Human Leukemia Cells Is Regulated by the Kinase Cdk5 and by Glucose. Molecular Cell, 2010. 40 (5): 823-833.
- Preview to Lowman et al article:
Gimenez-Cassina, A and N.N. Danial. Noxa: a Sweet Twist to Survival and more. Molecular Cell, 2010. 40 (5): 687-688.
- Codina, R., A. Vanasse, A. Kelekar, V. Vezys and R. Jemmerson. 2010. Cytochrome c-Induced Lymphocyte Death from the Outside In: Inhibition by Serum Leucine-Rich Alpha-2-Glycoprotein-1. Apoptosis, 15: 139-152.
- Bui Nguyen, T.M., I.V. Subramanian, X. Xue, G. Ghosh, P. Nguyen, A. Kelekar, and S. Ramakrishnan. 2009. Endostatin induces autophagy in endothelial cells by modulating Beclin-1 and b-catenin levels. Journal of Cellular and Molecular Medicine, 13:3687-3698.
- Kelekar, A. 2008. Edited and Introduced the Review Series Autophagy in Higher Eukaryotes- A matter of survival or death. Autophagy, 4 (5): 555 - 556.
- McDonnell, M. A., M. J. Abedin, M. Melendez, T. Platikanova, J. R. Ecklund, K. Ahmed, and A. Kelekar. 2008. Phosphorylation of Caspase-9 by Casein Kinase 2 regulates its cleavage by Caspase-8. 2008. Journal of Biological Chemistry 283 (29), 20149-20158 (E-pub ahead of print), May 8, 2008).
- Klionsky, D. et al. 2008. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy, 4(2):151-175.
- Ramakrishnan. S., T. Bui Nguyen, I. V Subramanian and A. Kelekar. 2007. Autophagy and Angiogenesis - an Addendum. Autophagy. 3:512-515.
- Zhao, Y.B., J. Altman, J.L. Coloff, C.E. Herman, S.R. Jacobs, H.L. Wieman, J.A. Wofford, L.N. Dimascio, O. Ilkayeva, A. Kelekar, T. Reya and J.C. Rathmell. 2007. GSK-3 alpha/beta Mediate a Glucose-Sensitive Anti-Apoptotic Signaling Pathway to Stabilize Mcl-1. Mol. Cell. Biol. 27:4328-4339.
- Abedin, M. J, D. Wang, M. A. McDonnell, U. Lehmann, and A. Kelekar. 2007. Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death and Differentiation. 14:500-510; advance online publication, September 22, 2006; di:10.1038/sj.cdd.4402039.
- Bui-Nguyen, T., I. V Subramanian, A. Kelekar and S. Ramakrishnan. 2007. Angiogenesis Inhibitor, Kringle 5 of human plasminogen, induces both autophagy and apoptotic death in endothelial cells. Blood 109(11):4793-802.
- Kelekar, A. 2005. Autophagy in Cell Injury: Mechanisms, Responses and Repair, Annals of the New York Academy of Sciences. 2006. 1066:1363.015.
- Goldstein, J. C., C. Muñoz-Pinedo, J-E. Ricci, S. R. Adams, A. Kelekar, M. Schuler, R. Y. Tsien, and D. R. Green. 2005. Cytochrome c is released in a single step during apoptosis. Cell Death and Differentiation 12, 453-462.
- Wang, D., M.A. McDonnell and A. Kelekar. 2005. Multi-probe RPA template sets to study RNA modulation and transcriptional control of BH3-only members of the Bcl-2 family. Cancer Detection and Prevention, 29:189-200.
- Ke, H., J. Pei, Z. Ni, H. Xia, H. Qi, T. Woods, A. Kelekar, and W. Tao. 2004. Putative tumor suppressor LATS2 induces apoptosis through down regulation of Bcl-2 and Bcl-xL. Experimental Cell Research, 298:329-338.
- Vallera D. A, N. Jin, Y. Shu, A. Panoskaltsis-Mortari, A. Kelekar, and W. Chen. 2003. Retroviral immunotoxin gene therapy of leukemia in mice using leukemia-specific T cells transduced with an IL-3/Bax hybrid gene. Human Gene Therapy 4:1787-98.
- McDonnell, M. A., D. Wang, S M. Khan, M. G. Vander Heiden, and A. Kelekar. 2003. Caspase-9 is activated in a cytochrome c-independent manner early during TNFa-induced apoptosis in murine cells. Cell Death and Differentiation. 10: 1005-1015.
- Kelekar, A. and C. B. Thompson. BH domains. The Encyclopedia of Molecular Medicine 2001. John Wiley & Sons, New York., pages 353-357.
- Kelekar, A. and C. B. Thompson. Bcl-2 proteins. The Encyclopedia of Molecular Medicine 2001, John Wiley & Sons, New York, pages 328-333.
- Kaspar A. A., S. Okada, J. Kumar, F. R. Poulain, K. A. Drouvalakis, A. Kelekar, D. A. Hanson, R. M. Kluck, Y. Hitoshi, D. E. Johnson, C. J. Froelich, C. B. Thompson, D. D. Newmeyer, A. Anel, C. Clayberger, and A. M. Krensky. 2001. A distinct pathway of cell-mediated apoptosis initiated by granulysin. J Immunol. 167: 350-356.
- Kelekar, A., B. S. Chang, M. H. Harris, J. E. Harlan, S. W. Fesik and C. B. Thompson.1999. The BH3 domain of Bcl-xS is required for the inhibition of the anti-apoptotic function of Bcl-xL. Mol. Cell. Biol. 19: 6673-6681.
- Pena, J. C., A. Kelekar, E. V. Fuchs and C. B. Thompson. 1999. Manipulation of outer root sheath survival perturbs the hair growth cycle. The EMBO Journal 18: 3596-3603.
- Minn, A. J., C. S. Kettlun, H. Liang, A. Kelekar, M. G. Vander Heiden, B. S. Chang, S. W. Fesik, M. Fill and C. B. Thompson. 1999. Bcl-xL regulates apoptosis by heterodimerization-dependent and heterodimerization-independent mechanisms. The EMBO Journal 18: 632-643.
- Kelekar, A. and C.B. Thompson. 1998. Bcl-2 Homology Domains: The role of the BH3 domain in apoptosis. Trends in Cell Biology 8: 324-330.
- Kelekar, A., B. S. Chang, J. E. Harlan, S. W. Fesik and C. B. Thompson. 1997. Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-xL. Mol. Cell. Biol. 17: 7040-7046.