Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 34, Issue 15, Pages 2857-2873Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00333-14
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Funding
- Pancreas Research Foundation of Japan
- [24590943]
- Grants-in-Aid for Scientific Research [24590943, 26293304, 25670352] Funding Source: KAKEN
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Hu antigen R (HuR) regulates stress responses through stabilizing and/or facilitating the translation of target mRNAs. human TRA2 beta gene encodes splicing factor transformer 2 beta (Tra2 beta) and generates 5 mRNA isoforms (TRA2 beta 1 to -5) through alternative splicing. Exposure of HCT116 colon cancer cells to sodium arsenite stimulated checkpoint kinase 2 (Chk2)- and mitogen-activated protein kinase p38 (p38(MAPK))-mediated phosphorylation of HuR at positions S88 and T118. This induced an association between HuR and the 39-nucleotide (nt) proximal region of TRA2 beta exon 2, generating a TRA2 beta 4 mRNA that includes exon 2, which has multiple premature stop codons. HuR knockdown or Chk2/p38(MAPK) double knockdown inhibited the arsenite-stimulated production of TRA2 beta 4 and increased Tra2 beta protein, facilitating Tra2 beta-dependent inclusion of exons in target pre-mRNAs. The effects of HuR knockdown or Chk2/p38(MAPK) double knockdown were also confirmed using a TRA2 beta minigene spanning exons 1 to 4, and the effects disappeared when the 39-nt region deleted from the minigene. In endogenous HuR knockdown cells, the overexpression of a HuR mutant that could not be phosphorylated (with changes of serine to alanine at position 88 [S88A], S100A, and T118A) blocked the associated TRA2 beta 4 interaction and TRA2 beta 4 generation, while the overexpression of a phosphomimetic HuR (with mutations S88D, S100D, and T118D) restored the TRA2 beta 4-related activities. Our findings revealed the potential role of nuclear HuR in the regulation of alternative splicing programs under oxidative stress.
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