Polyamines regulate the stability of activating transcription factor-2 mRNA through RNA-binding protein HuR in intestinal epithelial cells
Language: 
English
Abstract: 

Maintenance of intestinal mucosal epithelial integrity requires polyamines that modulate the expression of various genes involved in cell proliferation and apoptosis. Recently, polyamines were shown to regulate the subcellular localization of the RNA-binding protein HuR, which stabilizes its target transcripts such as nucleophosmin and p53 mRNAs. The activating transcription factor-2 (ATF-2) mRNA encodes a member of the ATF/CRE-binding protein family of transcription factors and was computationally predicted to be a target of HuR. Here, we show that polyamines negatively regulate ATF-2 expression posttranscriptionally and that polyamine depletion stabilizes ATF-2 mRNA by enhancing the interaction of the 3'-untranslated region (UTR) of ATF-2 with cytoplasmic HuR. Decreasing cellular polyamines by inhibiting ornithine decarboxylase (ODC) with alpha-difluoromethylornithine increased the levels of ATF-2 mRNA and protein, whereas increasing polyamines by ectopic ODC overexpression repressed ATF-2 expression. Polyamine depletion did not alter transcription via the ATF-2 gene promoter but increased the stability of ATF-2 mRNA. Increased cytoplasmic HuR in polyamine-deficient cells formed ribonucleoprotein complexes with the endogenous ATF-2 mRNA and specifically bound to 3'-UTR of ATF-2 mRNA on multiple nonoverlapping 3'-UTR segments. Adenovirus-mediated HuR overexpression elevated ATF-2 mRNA and protein levels, whereas HuR silencing rendered the ATF-2 mRNA unstable and prevented increases in ATF-2 mRNA and protein. Furthermore, inhibition of ATF-2 expression prevented the increased resistance of polyamine-deficient cells to apoptosis induced by treatment with tumor necrosis factor-alpha and cycloheximide. These results indicate that polyamines modulate the stability of ATF-2 mRNA by altering cytoplasmic HuR levels and that polyamine-modulated ATF-2 expression plays a critical role in regulating epithelial apoptosis.

Author(s): 
Xiao, Lan
Rao, Jaladanki N.
Zou, Tongtong
Liu, Lan
Marasa, Bernard S.
Chen, Jie
Turner, Douglas J.
Zhou, Huiping
Gorospe, Myriam
Wang, Jian-Ying
Item Type: 
Journal Article
Publication Title: 
Molecular Biology of the Cell
Journal Abbreviation: 
Mol. Biol. Cell
Publication Date: 
Nov 2007
Publication Year: 
2007
Pages: 
4579-4590
Volume: 
18
Issue: 
11
ISSN: 
1059-1524
DOI: 
10.1091/mbc.E07-07-0675
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 17804813 PMCID: PMC2043536

Turabian/Chicago Citation

Lan Xiao, Jaladanki N. Rao, Tongtong Zou, Lan Liu, Bernard S. Marasa, Jie Chen, Douglas J. Turner, Huiping Zhou, Myriam Gorospe and Jian-Ying Wang. Nov 2007. "Polyamines regulate the stability of activating transcription factor-2 mRNA through RNA-binding protein HuR in intestinal epithelial cells." Molecular Biology of the Cell 18: 11: 4579-4590. 10.1091/mbc.E07-07-0675.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1091/mbc.E07-07-0675 | issn = 1059-1524 | volume = 18 | pages = 4579-4590 | last = Xiao | first = Lan | coauthors = Rao, Jaladanki N., Zou, Tongtong, Liu, Lan, Marasa, Bernard S., Chen, Jie, Turner, Douglas J., Zhou, Huiping, Gorospe, Myriam, Wang, Jian-Ying | title = Polyamines regulate the stability of activating transcription factor-2 mRNA through RNA-binding protein HuR in intestinal epithelial cells | journal = Molecular Biology of the Cell | date = Nov 2007 | pmid = | pmc = }} </ref>