Assistant Professor, Department of Laboratory Medicine and Pathology

ameeta@umn.edu
612-625-3204 — office
612-626-2358 — lab
Preferred method of contact: e-mail

Dr. Kelekar received a Ph.D. in molecular biology from Princeton University in 1987. She conducted postdoctoral training (1987-1992) in microbiology/immunology in the laboratory of Dr. J.D. Keene at Duke University Medical Center. She then joined the laboratory Dr. Craig Thompson at the Howard Hughes Medical Institute, University of Chicago. She joined the faculty the Department of Laboratory Medicine & Pathology at the University of Minnesota in 2000.

Research Interests

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.

Selected Publications

McDonnell MA, Abedin MJ, Melendez M, Platikanova T, Ecklund JR, Ahmed K, Kelekar A. Phosphorylation of caspase-9 by casein kinase 2 regulates its cleavage by caspase-8. J Biol Chem. 2008 [E-pub ahead of print].

Klionsky D, et, al.  Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008;4:151-175.

Ramakrishnan S, Bui Nguyen T, Subramanian IV, Kelekar A. Autophagy and Angiogenesis - an Addendum. Autophagy. 2007;3:512-515.

Zhao Y, Altman BJ, Coloff JL, Herman CE, Jacobs SR, Wieman HL, Wofford JA, Dimascio LN, Ilkayeva O, Kelekar A, Reya T, Rathmell JC. GSK-3alpha/alpha mediate a glucose-sensitive anti-apoptotic signaling pathway to stabilize Mcl-1. Mol Cell Biol.2007 27:4328-4339

Bui-Nguyen T, Subramanian IV, Kelekar A, Ramakrishnan S. Kringle 5 of human plasminogen, induces both autophagy and apoptotic death in endothelial cells. Blood 2007;109:4793-4802.

Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A. Autophagy delays apoptotic death in DNA-damaged breast cancer cells. Cell Death Differ. 2007;14:500-510.

Kelekar A. Autophagy. Ann NY Acad Sc. 2006;1066:259-271.

Wang D, McDonnell MA, Kelekar A. Multi-probe RPA template sets to study RNA modulation and transcriptional control of BH3-only members of the Bcl-2 family. Cancer Detect Prevent. 2005;29:189-200.

Goldstein J C, Muñoz-Pinedo C, Ehrland-Ricci J, Adams S, Kelekar A, Schuler M, Tsien R, Green DR. Cytochrome c is released in a single step during apoptosis. Cell Death Differ. 2005;12:453-462.

Ke H, Pei J, Ni Z, Xia H, Qi H, Woods T, Kelekar A, Tao W. Putative tumor suppressor LATS2 induces apoptosis through down regulation of Bcl-2 and Bcl-xL. Exp Cell Res. 2004; 298:329-338.

Vallera DA, Jin N, Shu Y, Panoskaltsis-Mortari A, Kelekar A, Chen W. Retroviral immunotoxingene therapy of leukemia in mice using leukemia-specific T cells transduced with an IL-3/Bax hybridgene. Hum Gene Ther. 2003;14:1787-1798.

McDonnell MA, Wang D, Khan SM, Vander Heiden MG, Kelekar A. Caspase-9 is activated in a cytochrome c-independent manner early during TNF alpha-induced apoptosis in murine cells. Cell Death Differ. 2003;10:1005-1015.

Kelekar A, Thompson CB. BH domains. In: The Encyclopedia of Molecular Medicine 2001. John Wiley & Sons, New York, pages 353-357.

Kelekar A, Thompson CB. Bcl-2 proteins. In: The Encyclopedia of Molecular Medicine 2001, John Wiley & Sons, New York, pages 328-333.

Kaspar AA, Okada S, Kumar J, Poulain FR, Drouvalakis KA, Kelekar A, Hanson DA, Kluck RM, Hitoshi Y, Johnson DE, Froelich CJ, Thompson CB, Newmeyer DD, Anel A, Clayberger C, Krensky AM. A distinct pathway of cell-mediated apoptosis initiated by granulysin. J Immunol. 2001;167:350-356.