Shrikant Anant, Ph.D.

DEPARTMENT OF Internal Medicine
Keywords: cancer, host-pathogen interactions, mRNA stability, mRNA translation, RNA, signal transduction

Our laboratory is interested in understanding the role of nucleic acid binding proteins during inflammation and carcinogenesis. We have identified DNA- (NF-kB) and RNA-binding (HuR and CUGBP2) proteins that differentially regulate cyclooxygenase-2 (COX-2) expression during cancer progression and in chemoprevention. COX-2 is significantly induced in many tumors. In colon cancer cells, we have determined that NF-kB subunits c-Rel and RelA are differentially induced by epidermal growth factor resulting in increased COX-2 promoter activity. In addition, we have determined differential regulation of NF-kB subunits in response to Helicobacter pylori infection in gastric epithelial cells and selective induction of COX-2 promoter activity following RelA expression. COX-2 expression is also regulated at the post-transcriptional levels of mRNA stability and translation. We have recently identified that both radiation injury and dietary phytochemicals induce expression of the RNA-binding protein CUGBP2 in intestinal epithelial cells undergoing apoptosis. CUGBP2 is ubiquitously expressed in epithelial cells and its expression is lost in transition from a normal cell to adenoma. Following induction, CUGBP2 binds a variety of AU-rich RNAs, including c-myc, TNF-a, VEGF and COX-2. CUGBP2 binding to the AU-rich sequences in 3'UTR of COX-2 increases COX-2 mRNA stability but inhibits its translation, suggesting a unique role for CUGBP2 in mRNA stability and translation control. Overexpression of CUGBP2 in colon cancer cell lines results in the cells undergoing apoptosis, suggesting that CUGBP2 plays a critical role in modulating cellular proliferation.