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Molecular and Cellular Biology, March 2006, p. 2419-2429, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2419-2429.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Nucleolin-Binding 3' Untranslated Region Element Stabilizes ß-Globin mRNA In Vivo

Yong Jiang,1 Xiang-Sheng Xu,1 and J. Eric Russell1,2*

Departments of Medicine (Hematology/Oncology),1 Pediatrics (Hematology), University of Pennsylvania School of Medicine and The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania2

Received 6 July 2005/ Returned for modification 19 August 2005/ Accepted 14 December 2005

The normal expression of human ß globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with {alpha}-globin mRNA, the specific cis-acting determinants and trans-acting factors that participate in stabilizing ß-globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the ß-globin 3' untranslated region (3'UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by {alpha}CP/hnRNP-E, a factor that plays a critical role in stabilizing human {alpha}-globin mRNA. Mutations within the new determinant destabilize ß-globin mRNA in intact cells while also ablating its 3'UTR-specific interaction with the polyfunctional RNA-binding factor nucleolin. We speculate that 3'UTR-bound nucleolin enhances mRNA stability by optimizing {alpha}CP access to its functional binding site. This model is favored by in vitro evidence that {alpha}CP binding is enhanced both by cis-acting stem-destabilizing mutations and by the trans-acting effects of supplemental nucleolin. These studies suggest a mechanism for ß-globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human {alpha}-globin mRNA.

* Corresponding author. Mailing address: Abramson Research Building, Room 316F, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. Phone: (215) 590-3880. Fax: (215) 590-4834. E-mail: jeruss{at}mail.med.upenn.edu.

Molecular and Cellular Biology, March 2006, p. 2419-2429, Vol. 26, No. 6
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.6.2419-2429.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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