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Nucleolin Stabilizes Bcl-X_L Messenger RNA in Response to UVA Irradiation

¹ Arizona Cancer Center and ² Center for Toxicology, University of Arizona, Tuczon, Arizona

Requests for reprints: G. Tim Bowden, Arizona Cancer Center, University of Arizona, 1515 N. Campbell, Tucson, AZ 85724. Phone: 520-626-6006; Fax: 520-626-4979; E-mail: tbowden{at}azcc.arizona.edu.

Key Words: Bcl-X_L • nucleolin • apoptosis • mRNA stabilization

Our laboratory has previously reported that UVA irradiation can increase the expression of Bcl-X_L, an antiapoptotic molecule, by stabilizing its mRNA in cultured immortalized human keratinocytes. To understand the mechanism by which the Bcl-X_L message is stabilized, we used a synthetic Bcl-X_L 3'-untranslated region (UTR) to capture RNA-binding proteins. Nucleolin was identified as one of the binding proteins as determined by tandem mass spectrometry coupled to liquid chromatography analysis. Further study showed that nucleolin specifically recognized the AU-rich elements (AUUUA) in the 3'-UTR of the Bcl-X_L mRNA and could stabilize the mRNA in vitro. Furthermore, overexpression of nucleolin stabilizes the Bcl-X_L mRNA in HeLa cells, whereas reducing nucleolin by small interfering RNA shortens the Bcl-X_L mRNA half-life. Interestingly, nucleolin physically interacted with polyadenylate [poly(A)]–binding protein through it RGG motifs. Its stabilizing effect on the Bcl-X_L mRNA was dependent upon the presence of poly(A) tail. Based on these data, we propose a model in which nucleolin protects the Bcl-X_L mRNA from nuclease degradation by enhancing the stability of the ribonucleoprotein loop structure. [Cancer Res 2008;68(4):1046–54]