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Novel intestinal splice variants of RNA-binding protein CUGBP2: isoform-specific effects on mitotic catastrophe.
- Source :
- American Journal of Physiology: Gastrointestinal & Liver Physiology; Apr2008, Vol. 294, pG971-G981, 11p, 16 Black and White Photographs, 1 Diagram, 18 Graphs
- Publication Year :
- 2008
-
Abstract
- CUG triplet repeat-binding protein 2 (CUGBP2) is a RNA-binding protein that regulates mRNA translation and modulates apoptosis. Here, we report the identification of two splice variants (termed variants 2 and 3) in cultured human intestinal epithelial cells and in mouse gastrointestinal tract. The variants are generated from alternative upstream promoters resulting in the inclusion of additional NH<subscript>2</subscript>-terminal residues. Although variant 2 is the predominant isoform in normal intestine, its expression is reduced, whereas variant 1 is overexpressed following γ-irradiation. All three variants bind cyclooxygenase-2 (COX-2) mRNA. However, only variant 1 inhibits the translation of the endogenous COX-2 mRNA and a chimeric luciferase mRNA containing the COX-2 3′untranslated region. Furthermore, whereas variant 1 is predominantly nuclear, variants 2 and 3 are predominantly cytoplasmic. These data imply that the additional amino acids affect CUGBP2 function. Previous studies have demonstrated that variant 1 induces intestinal epithelial cells to undergo apoptosis. However, in contrast to variant 1, the two novel variants do not affect proliferation or apoptosis of HCT116 cells. In addition, only variant 1 induced G<subscript>2</subscript>/M cell cycle arrest, which was overcome by prostaglandin E<subscript>2</subscript>. Moreover, variant 1 increased cellular levels of phosphorylated p53 and Bax and decreased Bcl2. Caspase-3 and -9 were also activated, suggesting the initiation of the intrinsic apoptotic pathway. Furthermore, increased phosphorylation of checkpoint kinase (Chk) 1 and Chk2 kinases and increased nuclear localization of Cdc2 and cyclin B1 suggested that cells were in mitotic transition. Taken together, these data demonstrate that cells expressing CUGBP2 variant 1 undergo apoptosis during mitosis, suggesting mitotic catastrophe. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01931857
- Volume :
- 294
- Database :
- Complementary Index
- Journal :
- American Journal of Physiology: Gastrointestinal & Liver Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 31956244
- Full Text :
- https://doi.org/10.1152/ajpgi.00540.2007