Vivek Rangnekar, Ph.D.

Professor

Selected publications

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.