Ultraviolet radiation (UVR) activates p38 MAP kinase and induces post-transcriptional stabilization of the C/EBPdelta mRNA in G0 growth arrested mammary epithelial cells.
The G(0) growth arrest (quiescent) state is highly conserved in evolution to promote survival under adverse environmental conditions. To maintain viability, G(0) growth arrested cells limit gene expression to essential growth control and pro-survival genes. CCAAT enhancer binding protein delta (C/EBPdelta), a member of the C/EBP family of nuclear proteins, is highly expressed in G(0) growth arrested mammary epithelial cells (MECs). Although C/EBPdelta gene transcription is elevated during G(0) growth arrest, C/EBPdelta mRNA and protein are relatively short lived, suggesting tight control of the cellular C/EBPdelta content in unstressed, quiescent cells. Treatment of G(0) growth arrested MECs with ultraviolet radiation (UVR) dramatically increases the C/EBPdelta mRNA half-life (approximately 4-fold) and protein content (approximately 3-fold). The mRNA stabilizing effects of UVR treatment are mediated by the C/EBPdelta mRNA 3'untranslated region, which contains an AU rich element. UVR increased p38 MAP kinase (MAPK) activation and SB203580, a p38 MAPK inhibitor, blocked UVR-induced C/EBPdelta mRNA stabilization. UVR increased the nuclear to cytoplasmic translocation of HuR, an ARE-binding protein that functions in mRNA stabilization. Finally, HuR siRNA treatment blocked UVR-induced stabilization of the C/EBPdelta and C/EBPbeta mRNAs but had no effect on C/EBPzeta (CHOP) mRNA stability. In summary, G(0) growth arrested MECs respond to UVR treatment by activating p38 MAPK, increasing HuR translocation and HuR/C/EBPdelta mRNA binding and stabilizing the C/EBPdelta mRNA. These results identify post-transcriptional stabilization of the C/EBPdelta mRNA as a mechanism to increase C/EBPdelta levels in the stress response of quiescent cells to UVR.
Li
Bin
B
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Si
Junling
J
DeWille
James W
JW
D020413:3' Untranslated Regions / Q000378:metabolism; D000818:Animals; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000096:biosynthesis*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006207:Half-Life; D007093:Imidazoles / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D011725:Pyridines / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects / Q000528:radiation effects*; D016601:RNA-Binding Proteins / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000528:radiation effects*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D020413:3' Untranslated Regions; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016601:RNA-Binding Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580