Vivek Rangnekar,
Professor
Radiation Medicine
http://www.mc.uky.edu/microbiology/rangnekar.asp
Phone:
(859) 257-2677
Fax:
(859) 257-8940
e-mail:
vmrang01@uky.edu
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Research Interests
My laboratory studies transcriptional regulation of apoptosis. Our work
focuses on tumor suppressor and pro-apoptotic genes, with the objective of
delineating the mechanism underlying the regulation and function of the
genes in normal and cancer cells. Specifically, we work on two
pro-apoptotic genes: Par-4 and PTEN.
The Par-4 gene was identified first by my laboratory in 1993. Studies thus
far have indicated that Par-4 is a transcriptional repressor with a unique
SAC domain, which is involved in selective apoptosis of cancer cells but
not normal cells. Cells that are resistant to the direct apoptotic action
of Par-4 become sensitized to apoptosis by diverse apoptotic insults (for
example, intracellular calcium elevation, ionizing radiation,
chemotherapeutic agents, cytokines TNF & TRAIL, and neurodegenerative
signals). Moreover, Par-4 expression is suppressed by oncogenes, and
restoration of Par-4 prevents cellular transformation by a mechanism that
is distinct from its pro-apoptotic function. To elucidate the mechanism by
which Par-4 induces apoptosis, apoptosis-sensitization, or transformation
inhibition, we are studying various targets of Par-4 that were identified
by the gene micro-array technology for a functional role in Par-4 action.
A key component of the studies addresses the role of phosphorylation sites
and protein binding partners in nucleo-cytoplasmic trafficking of Par-4.
Because Par-4 selectively induces apoptosis in cancer cells and can shrink
solid tumors in animals, it is being developed for molecular therapy of
cancer.
PTEN is the master tumor suppressor commonly deleted, mutated or
down-regulated in cancer. Our laboratory has identified a novel mechanism
of PTEN gene suppression by molecules that are commonly activated in
cancer cells. This project involves characterization of the PTEN promoter
for motifs responding to transcriptional repression by using chromatin-immunoprecipitation
(ChIP) technology. The potential transcriptional factors involved are
blocked by using dominant-negative and siRNA approaches, in order to
elucidate the upstream pathways for PTEN gene regulation. The studies
should offer novel insights into the regulation of the PTEN gene, and
allow the identification of molecules for intervention strategies.
Research Publications/Presentations
1. N. El-Guendy, Y. Zhao, S. Gurumurthy, R. Burikhanov, and V. M.
Rangnekar (2003) Identification of a unique core domain of Par-4
sufficient for selective apoptosis-induction in cancer cells. Mol.
Cell. Biol. 23: 5516-5525.
2. J. Butler and V. M. Rangnekar (2003) Par-4 for molecular therapy of
prostate cancer (review). Current
Drug Targets. 4: 223-230.
3. K. M. Vasudevan,S. Gurumurthy, and V. M. Rangnekar. (2004)
Suppression of PTEN Expression by NF-kappaB Prevents Apoptosis. Mol.
Cell. Biol. 24: 1007–1021.
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