Posttranscriptional control of gene expression plays a key role in regulating gene expression in cells undergoing apoptosis. Cyclooxygenase-2 (COX-2) is a crucial enzyme in the conversion of arachidonic acid to prostaglandin E2 (PGE(2)) and is significantly upregulated in many types of adenocarcinomas. COX-2 overexpression leads to increased PGE(2) production, resulting in increased cellular proliferation. PGE(2) enhances the resistance of cells to ionizing radiation. Accordingly, understanding mechanisms regulating COX-2 expression may lead to important therapeutic advances. Besides transcriptional control, COX-2 expression is significantly regulated by mRNA stability and translation. We have previously demonstrated that RNA binding protein CUGBP2 binds AU-rich sequences to regulate COX-2 mRNA translation. In the current study, we have determined that expression of both COX-2 mRNA and CUGBP2 mRNA are induced in MCF-7 cells, a breast cancer cell line, following exposure to 12 Gy gamma-irradiation. However, only CUGBP2 protein is induced, but COX-2 protein levels were not altered. Silencer RNA (siRNA)-mediated inhibition of CUGBP2 reversed the block in COX-2 protein expression. Furthermore, MCF-7 cells underwent apoptosis in response to radiation injury, which was also reversed by CUGBP2 siRNAs. These data suggest that CUGBP2 is a critical regulator of the apoptotic response to genotoxic injury in breast cancer cells.