CUGBP2 plays a critical role in apoptosis of breast cancer cells in response to genotoxic injury.
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.
Mukhopadhyay
Debnath
D
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Jung
Jesse
J
Murmu
Nabendu
N
Houchen
Courtney W
CW
Dieckgraefe
Brian K
BK
Anant
Shrikant
S
D001943:Breast Neoplasms / Q000473:pathology*; D000067878:CELF Proteins; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D004307:Dose-Response Relationship, Radiation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D012323:RNA Processing, Post-Transcriptional; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D000067878:CELF Proteins; C117363:CELF2 protein, human; D007527:Isoenzymes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases