Coupled mRNA stabilization and translational silencing of cyclooxygenase-2 by a novel RNA binding protein, CUGBP2.
Cyclooxygenase-2 (COX-2) expression is translationally silenced in epithelial cells undergoing radiation-induced apoptosis. CUGBP2, a predominantly nuclear protein, is also rapidly induced in response to radiation and translocates to the cytoplasm. Antisense-mediated suppression of CUGBP2 renders radioprotection through a COX-2-dependent prostaglandin pathway, providing an in vivo demonstration of translation inhibition activity for CUGBP2. CUGBP2 binds to two sets of AU-rich sequences (AREs) located within the first sixty nucleotides of the COX-2 3' untranslated region (3'UTR). Upon binding, CUGBP2 stabilizes a chimeric luciferase-COX-2 3'UTR mRNA but inhibits its translation. These findings identify a novel paradigm for RNA binding proteins in facilitating opposing functions of mRNA stability and translation inhibition and reveal a mechanism for inhibiting COX-2 expression in cancer cells.
Mukhopadhyay
Debnath
D
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Houchen
Courtney W
CW
Kennedy
Susan
S
Dieckgraefe
Brian K
BK
Anant
Shrikant
S
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D001483:Base Sequence; D000067878:CELF Proteins; D051546:Cyclooxygenase 2; D004847:Epithelial Cells / Q000502:physiology / Q000528:radiation effects; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D014466:Ultraviolet Rays
D020413:3' Untranslated Regions; D000067878:CELF Proteins; C117363:CELF2 protein, human; D007527:Isoenzymes; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases