The RNA-binding protein HuR stabilizes survivin mRNA in human oesophageal epithelial cells

Abstract

Overexpression of survivin, a member of the IAP (inhibitor of apoptosis) family, has been correlated with poorer outcomes in multiple malignancies, including oesophageal cancer. The regulatory mechanisms, particularly at the post-transcriptional level, involved in survivin overexpression are not well understood. Previous work from our group has shown that the RNA-binding protein HuR (Hu antigen R), which is also overexpressed in several malignancies, stabilizes the mRNA of XIAP (X-linked IAP), another IAP family member. In the present study, we demonstrate the binding of HuR to a 288 bp fragment in the 3'-UTR (untranslated region) of survivin mRNA in human oesophageal epithelial cells. Unexpectedly, overexpression of HuR led to a decrease in survivin expression. This was associated with decreased survivin mRNA and promoter activity, suggesting a decrease in transcription. Levels of p53, a negative transcriptional regulator of survivin, increased following HuR overexpression, in conjunction with enhanced p53 mRNA stability. Silencing p53 prior to HuR overexpression resulted in increased survivin protein and mRNA stability. These results demonstrate that, in the absence of p53, HuR overexpression results in increased survivin mRNA stability and protein expression. This provides an additional explanation for the increased survivin expression observed in oesophageal cancer cells that have lost p53.

Regulation of Monocarboxylate Transporter MCT1 Expression by p53 Mediates Inward and Outward Lactate Fluxes in Tumors

“…Mechanistically, we showed that the lack of P53 was associated with the stabilization of the MCT1 mRNA transcript in response to hypoxia, suggesting that, when present, P53 could act as a repressor of MCT1 expression. A similar mode of regulation was recently reported for survivin, the mRNA stability of which being increased in the absence of p53 (34). Moreover, our ChIP experiments confirmed the direct interaction of both P53 and the corepressor mSin3A with the MCT1 gene.…”

AU-rich RNA binding proteins in hematopoiesis and leukemogenesis

“…It stabilizes mRNAs encoding BCL2, MCL1, cyclin A, cyclin B1, cyclin D1, lymphotoxin-␣, GM-CSF, IL4, VEGF, CD3, CD95L, GATA-3, XIAP, and survivin. [23][24][25][26][27][28][29][30] HUR has also been reported to destabilize mRNAs for AML1/RUNX1, CD2, VAV1, NFBIE, CD3⑀, TNF␣, and STAT3. 27 HUR enhances the translational efficiency of mRNAs encoding p53, cytochrome c, XIAP, and BCL2 while suppressing translation of p27, MYC, and WNT5␣.…”

“…This suggests that the outcome of HUR expression on survivin levels may depend on the p53 mutational status of leukemic cells. 23 Finally, HuR have been implicated in posttranscriptional genotoxic/oxidative stress pathways in mammalian cells, 47 and recent data havew shown that it functions as a key mediator of the checkpoint kinase, ataxia telangiectasia mutated (ATM) in B lymphocyte cell lines. 48 In response to double-stranded DNA breaks, the ATM kinase phosphorylates a cascade of downstream effectors, including the checkpoint kinase CHK2, which in turn phosphorylates HUR to modulate its mRNA-binding and translational control functions.…”

“…Overexpression of HUR results in inhibition of p53-dependent transcription and down-regulation of expression of the survivin protein. 23 HUR stabilizes p53 mRNA leading to increased levels of p53 protein, which in turn negatively regulates survivin gene transcription. However, when p53 is silenced, HUR overexpression actually increases levels of survivin by stabilizing its mRNA.…”

The RNA-binding protein CUG-BP1 increases survivin expression in oesophageal cancer cells through enhanced mRNA stability

“…Instead, IGF-1 was found to modulate improved stability and enhanced translation of a pre-existing pool of survivin mRNA, although the mechanism by which this occurred was not elucidated. Finally, we have recently shown that the RBP HuR bound to the 3′UTR of survivin mRNA and prolonged its half-life in esophageal epithelial cells [19]. However, this interaction proved to be quite complex, as HuR overexpression in these cells also increased levels of p53, leading to decreased survivin transcription.…”