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J. Biol. Chem., Vol. 281, Issue 28, 19387-19394, July 14, 2006

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Polyamine Depletion Increases Cytoplasmic Levels of RNA-binding Protein HuR Leading to Stabilization of Nucleophosmin and p53 mRNAs^*

Tongtong Zou, Krystyna Mazan-Mamczarz^¶1, Jaladanki N. Rao, Lan Liu, Bernard S. Marasa^||, Ai-Hong Zhang, Lan Xiao, Rudolf Pullmann^¶1, Myriam Gorospe^¶1, and Jian-Ying Wang^||2

From the Cell Biology Group, Department of Surgery and the ^||Department of Pathology, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201 and the ^¶Laboratory of Cellular and Molecular Biology, NIA-IRP, National Institutes of Health, Baltimore, Maryland 21224

Polyamines are essential for maintaining normal intestinal epithelial integrity, an effect that relies, at least in part, on their ability to keep low levels of nucleophosmin (NPM) and p53 mRNAs. The RNA-binding protein HuR associates with the p53 mRNA, as reported previously, and with the NPM mRNA, computationally predicted to be a target of HuR. Here, we show that HuR binds the NPM and p53 3'-untranslated regions and stabilizes these mRNAs in polyamine-depleted intestinal epithelial cells. Depletion of cellular polyamines by inhibiting ornithine decarboxylase with -difluoromethylornithine dramatically enhanced the cytoplasmic abundance of HuR, whereas ectopic ornithine decarboxylase overexpression decreased cytoplasmic HuR; neither intervention changed whole-cell HuR levels. HuR was found to specifically bind the 3'-untranslated regions of NPN and p53 mRNAs. HuR silencing rendered the NPM and p53 mRNAs unstable and prevented increases in NPM and p53 mRNA and protein in polyamine-deficient cells. These results indicate that polyamines modulate cytoplasmic HuR levels in intestinal epithelial cells, in turn controlling the stability of the NPM and p53 mRNAs and influencing NPM and p53 protein levels.

Received for publication, March 13, 2006 , and in revised form, May 8, 2006.

^* This work was supported by a Merit Review Grant from the Department of Veterans Affairs and by National Institutes of Health Grants DK-57819, DK-61972, and DK-68491. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the NIA-IRP, National Institutes of Health.

² A Research Career Scientist, Medical Research Service, U. S. Department of Veterans Affairs. To whom correspondence should be addressed: Surgical Service, Baltimore Veterans Affairs Medical Center, 10 North Greene St., Baltimore, MD 21201. Tel.: 410-605-7000, Ext. 5678; Fax: 410-605-7919; E-mail: jwang{at}smail.umaryand.edu.

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