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

2012 ◽  
Vol 446 (1) ◽  
pp. 113-123 ◽  
Author(s):  
Elizabeth T. Chang ◽  
James M. Donahue ◽  
Lan Xiao ◽  
Yuhong Cui ◽  
Jaladanki N. Rao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cancer Cells ◽  
Oesophageal Cancer ◽  
Mrna Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Survivin Expression ◽  
Survivin Mrna ◽  
Induced Apoptosis

Survivin, a member of the IAP (inhibitor of apoptosis protein) family, plays important roles in maintaining cellular homoeostasis and regulating cell-cycle progression. This IAP is overexpressed in oesophageal cancer cells, leading to uncontrolled cell growth and resistance to apoptosis. CUG-BP1 (CUG-binding protein 1) is an RNA-binding protein that regulates the stability and translational efficiency of target mRNAs. In the present paper, we report that CUG-BP1 is overexpressed in oesophageal cancer cell lines and human oesophageal cancer specimens. CUG-BP1 associates with the 3′-untranslated region of survivin mRNA, thereby stabilizing the transcript and elevating its expression in oesophageal cancer cells. Our results show that overexpression of CUG-BP1 in oesophageal epithelial cells results in increased survivin mRNA stability and consequently survivin protein expression. Conversely, silencing CUG-BP1 in oesophageal cancer cells destabilizes survivin mRNA, lowering the level of survivin protein. In addition, we have found that altering CUG-BP1 expression modulates susceptibility to chemotherapy-induced apoptosis. Overexpression of CUG-BP1 in oesophageal epithelial cells increases resistance to apoptosis, whereas silencing CUG-BP1 makes oesophageal cancer cells more susceptible to chemotherapy-induced apoptosis. Co-transfection experiments with small interfering RNA directed against survivin suggest that the anti-apoptotic role for CUG-BP1 is not entirely dependent on its effect on survivin expression.

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

2011 ◽  
Vol 437 (1) ◽  
pp. 89-96 ◽  
Author(s):  
James M. Donahue ◽  
Elizabeth T. Chang ◽  
Lan Xiao ◽  
Peng-Yuan Wang ◽  
Jaladanki N. Rao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Oesophageal Cancer ◽  
Mrna Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Survivin Expression ◽  
Transcriptional Level ◽  
Survivin Mrna ◽  
Hu Antigen R

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.

Abstract 3078: CD44 mRNA stability is regulated by RNA binding protein HuR in ovarian cancer cells

2011 ◽  
Author(s):  
Karl E. Miletti-Gonzalez ◽  
Christine L. Hostetter ◽  
Abhilash K. Ravindranath ◽  
Neelakandan Muthukumaran ◽  
Judith C. Keen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Mrna Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Ovarian Cancer Cells

scholarly journals Transcriptional regulation of importin-α1 by JunD modulates subcellular localization of RNA-binding protein HuR in intestinal epithelial cells

2016 ◽  
Vol 311 (6) ◽  
pp. C874-C883 ◽  
Author(s):  
Yan Xu ◽  
Jie Chen ◽  
Lan Xiao ◽  
Hee Kyoung Chung ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Subcellular Localization ◽  
Rna Binding ◽  
Nuclear Translocation ◽  
Intestinal Epithelial Cells ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Intestinal Epithelial ◽  
Mucosal Regeneration ◽  
Importin Α

The RNA-binding protein HuR is crucial for normal intestinal mucosal regeneration by modulating the stability and translation of target mRNAs, but the exact mechanism underlying HuR trafficking between the cytoplasm and nucleus remains largely unknown. Here we report a novel function of transcription factor JunD in the regulation of HuR subcellular localization through the control of importin-α1 expression in intestinal epithelial cells (IECs). Ectopically expressed JunD specifically inhibited importin-α1 at the transcription level, and this repression is mediated via interaction with CREB-binding site that was located at the proximal region of importin-α1 promoter. Reduction in the levels of importin-α1 by JunD increased cytoplasmic levels of HuR, although it failed to alter whole cell HuR levels. Increased levels of endogenous JunD by depleting cellular polyamines also inhibited importin-α1 expression and increased cytoplasmic HuR levels, whereas JunD silencing rescued importin-α1 expression and enhanced HuR nuclear translocation in polyamine-deficient cells. Moreover, importin-α1 silencing protected IECs against apoptosis, which was prevented by HuR silencing. These results indicate that JunD regulates HuR subcellular distribution by downregulating importin-α1, thus contributing to the maintenance of gut epithelium homeostasis.

scholarly journals Double-Stranded RNA-Binding Protein Regulates Vascular Endothelial Growth Factor mRNA Stability, Translation, and Breast Cancer Angiogenesis

2007 ◽  
Vol 28 (2) ◽  
pp. 772-783 ◽  
Author(s):  
Frank Vumbaca ◽  
Kathryn N. Phoenix ◽  
Daniel Rodriguez-Pinto ◽  
David K. Han ◽  
Kevin P. Claffey
Keyword(s):  
Breast Cancer ◽  
Mrna Stability ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Vascular Endothelial ◽  
Vegf Mrna ◽  
Double Stranded Rna ◽  
Hypoxic Conditions ◽  
Endothelial Growth Factor

ABSTRACT Vascular endothelial growth factor (VEGF) is a key angiogenic factor expressed under restricted nutrient and oxygen conditions in most solid tumors. The expression of VEGF under hypoxic conditions requires transcription through activated hypoxia-inducible factor 1 (HIF-1), increased mRNA stability, and facilitated translation. This study identified double-stranded RNA-binding protein 76/NF90 (DRBP76/NF90), a specific isoform of the DRBP family, as a VEGF mRNA-binding protein which plays a key role in VEGF mRNA stability and protein synthesis under hypoxia. The DRBP76/NF90 protein binds to a human VEGF 3′ untranslated mRNA stability element. RNA interference targeting the DRBP76/NF90 isoform limited hypoxia-inducible VEGF mRNA and protein expression with no change in HIF-1-dependent transcriptional activity. Stable repression of DRBP76/NF90 in MDA-MB-435 breast cancer cells demonstrated reduced polysome-associated VEGF mRNA levels under hypoxic conditions and reduced mRNA stability. Transient overexpression of the DRBP76/NF90 protein increased both VEGF mRNA and protein levels synthesized under normoxic and hypoxic conditions. Cells with stable repression of the DRBP76/NF90 isoform showed reduced tumorigenic and angiogenic potential in an orthotopic breast tumor model. These data demonstrate that the DRBP76/NF90 isoform facilitates VEGF expression by promoting VEGF mRNA loading onto polysomes and translation under hypoxic conditions, thus promoting breast cancer growth and angiogenesis in vivo.

Sign in / Sign up

Export Citation Format

Share Document