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Ameeta Kelekar, Ph.D.
Assistant Professor
Department of Laboratory Medicine and Pathology
Princeton University, 1987, Ph.D.
ameeta@umn.edu
612-625-3204 - office
612-626-2358 - lab
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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 –
1) 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.
2) 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 Recent Publications:
- Codina, R., A. Vanasse, A. Kelekar, V. Vezys and R. Jemmerson.
2009. Cytochrome c-Induced Lymphocyte Death from the Outside
In: Inhibition by Serum Leucine-Rich Alpha-2-Glycoprotein-1.
Apoptosis (in press).
- 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 (in press).
- 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.
- 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.
- 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. Abstract
- 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., 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.
Last modified on: February 23, 2009 |
