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C.B. Srikant, Ph.D. Associate Professor Department of Medicine Division of Endocrinology & Metabolism Fraser Laboratories, Room H5.41 |
Research:
G protein coupled receptors, somatostatin receptors.
My research interests encompass the pharmacological and functional properties of G protein coupled receptors (GPCR). The focus of my current research is the elucidation of the mechanism of antiproliferative action of the neuropeptide somatostatin (SST) and its receptor (SSTR) subtype selectivity for such signaling. Our findings have established that SST exerts cytotoxic action causing apoptosis in estrogen responsive breast cancer cells and in pituitary tumor cells. Its action is SHP-1-dependent and leads to induction of p53, Bax, an acidic endonuclease and decrease in intracellular pH. Inhibition of acidification prevents SST-induced apoptosis distal to changes in SHP-1, p53 and Bax. SST exerts cytotoxic action uniquely via hSSTR3 whereas it elicits cytostatic response by inducing (hypophosphorylated) Rb and G1 arrest via other hSSTRs (hSSTR5>2>4>1). These findings imply the potential therapeutic utility of SST analogs in oncology, but with varied outcome depending on the relative abundance of the SSTR, and the mediators of apoptosis and cell cycle in a given tumor. Elucidation of the mechanisms underlying SHP-1-dependent antiproliferative signaling and cellular pH homeostasis should help understand mechanism(s) of subtype-selective SSTR initiated antiproliferative signaling and help develop a rational approach to cancer therapy that targets GPCR mediated antiproliferative signaling.
Selected Publications:
Sharma, K., Patel, Y.C. and Srikant, C.B. Subtype selective induction of p53 and apoptosis but not cell cycle arrest by human somatostatin receptor 3. Mol. Endocrinol. 10: 1688-1696, 1996.
Sharma, K.S. and Srikant, C.B. G protein receptor signaled apoptosis is associated with activation of a cation insensitive acidic endonuclease and intracellular acidification. Biochem. Biophys. Res. Commun. 242: 134-140, 1998.
Sharma, K. and Srikant, C.B. Tumor cell apoptosis signaled via somatostatin receptor is associated with induction of wild type p53, Bax and endonuclease II. Int. J. Cancer 76: 259-266, 1998.
Sharma, K., Patel, Y.C. and Srikant, C.B. C-terminal region of human somatostatin receptor 5 is required for induction of retinoblastoma protein and G1 cell cycle arrest. Mol. Endocrinol. In press 1998.