TY - JOUR
T1 - CUGBP2 Plays a Critical Role in Apoptosis of Breast Cancer Cells in Response to Genotoxic Injury
AU - Mukhopadhyay, Debnath
AU - Jung, Jesse
AU - Murmu, Nabendu
AU - Houchen, Courtney W.
AU - Dieckgraefe, Brian K.
AU - Anant, Shrikant
PY - 2003
Y1 - 2003
N2 - 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 (PGE2) 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 γ-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.
AB - 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 (PGE2) 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 γ-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.
KW - AU-rich sequence
KW - Cyclooxygenase-2
KW - RNA binding proteins
KW - Radiation-induced injury
UR - https://www.scopus.com/pages/publications/1342347854
U2 - 10.1196/annals.1299.093
DO - 10.1196/annals.1299.093
M3 - Article
C2 - 15033780
AN - SCOPUS:1342347854
SN - 0077-8923
VL - 1010
SP - 504
EP - 509
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
ER -