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Office: (859) 257-2677
Fax: (859) 257-9608
Lab: (859) 257-4957
Email: vmrang01@uky.edu
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Vivek Rangnekar, Ph.D.
Professor
Doctoral Studies: University of Bombay, India.
Postdoctoral: University of Chicago.
Research Statement:
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.
Grants:
Mechanism of Apoptosis and Inhibition of Tumor Progression and Metastasis by Par-4
Source: NIH/NCI. From 07/01/08 to 06/31/13
Activation of the Par-4 Extrinsic Pathway for Suppression of Lung Cancer
Source: Kentucky Lung Cancer Research Program. From 12/01/2010 to 11/30/2012
Selected Recent Publications:
Burikhanov R, Shresta-Bhattarai T, Qiu S, Shukla N, Hebbar N, Lele SM, Horbinski C, Rangnekar VM. Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4. Cancer Res. 2012 Nov 30. [PDF]
Y. Zhao, R. Burikhanov, J. Brandon, S. Qiu, B.J. Shelton, B. Spear, S. Bondada, S. Bryson, and V.M. Rangnekar (2011) Systemic Par-4 inhibits non-autochthonous tumor growth. Cancer Biol Ther. 12(2):152-157. [PDF], News Release
T. Shrestha-Bhattarai and V.M. Rangnekar (2010) Cancer-selective apoptotic effects of extracellular and intracellular Par-4. Oncogene 29: 3873–3880. [PDF]
R. Burikhanov, Y. Zhao, A. Goswami, S. Qiu, S. Schwarze, and V. M. Rangnekar. (2009) The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis. Cell 138: 377-388. doi:10.1016/j.cell.2009.05.022.
A. Goswami, S. Qiu, T. S. Dexheimer, P. Ranganathan, R. Burikhanov, Y. Pommier and V. M. Rangnekar. (2008) Par-4 binds to topoisomerase 1 and attenuates its DNA relaxation activity. Cancer Res. 68: 6190-6198. [PDF]
Yanming Zhao, Ravshan Burikhanov, Shirley Qiu, Subodh M. Lele, C. Darrell Jennings, Subbarao Bondada, Brett Spear, and Vivek M. Rangnekar (2007) Cancer resistance in transgenic mice expressing the SAC module of Par-4. Cancer Res 67: 9276-9285. doi: 10.1158/0008-5472.CAN-07-2124 [PDF]
Krishna Murthi Vasudevan, Ravshan Burikhanov, Anindya Goswami, and Vivek M. Rangnekar (2007) Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras. Cancer Res 67: 10343-10350. doi: 10.1158/0008-5472.CAN-07-1827 [PDF]
A. Goswami, R. Burikhanov, A. de Thonel, N. Fujita, M. Goswami, Y. Zhao, J. E. Eriksson, T. Tsuruo, and V. M. Rangnekar (2005) Binding and phosphorylation of Par-4 by Akt is essential for cancer cell survival. Molecular Cell 20, 33–44. [Article]
Gurumurthy S, Goswami A, Vasudevan KM, Rangnekar VM. (2005) Phosphorylation of Par-4 by protein kinase A is critical for apoptosis. Mol Cell Biol. 25:1146-61 [Abstract]
N. El-Guendy and V. M. Rangnekar. (2003) Apoptosis by Par-4 in cancer and neurodegenerative diseases. (review) Experimental Cell Research 283: 51-66 [Abstract]
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 [PDF]
J. Butler and V. M. Rangnekar (2003) Par-4 for molecular therapy of prostate cancer (review). Current Drug Targets. 4: 223-230
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. [Abstract]
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