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J. Biol. Chem., Vol. 279, Issue 32, 33359-33367, August 6, 2004

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Selective Cytoplasmic Translocation of HuR and Site-specific Binding to the Interleukin-2 mRNA Are Not Sufficient for CD28-mediated Stabilization of the mRNA^*

Yuko Seko, Hooman Azmi, Robert Fariss, and Jack A. Ragheb¶

From the Laboratory of Immunology and the Biological Imaging Core, NEI, National Institutes of Health, Bethesda, Maryland 20892

The interleukin-2 mRNA is a labile transcript containing AU-rich elements that is transiently stabilized by CD28 receptor signaling. For a number of proto-oncogenes and cytokines, the HuR protein has been shown to avidly bind the AU-rich elements that confer instability upon their mRNAs. HuR was originally thought to participate in mRNA degradation but subsequent studies indicated that it actually functions to stabilize mRNA. Binding of HuR to the mouse interleukin-2 mRNA has not been studied. We tested if HuR binds the interleukin-2 mRNA and whether such binding is related to CD28-mediated stabilization of the mRNA. First, we confirm that T cell receptor signaling, which is sufficient to induce interleukin-2 transcription, also triggers translocation of HuR from the nucleus to the cytoplasm. Interestingly, T cell receptor-triggered translocation is selective as heterogeneous nuclear ribonucleoprotein A1 does not shuttle under the same conditions. Engagement of both the T cell and CD28 receptors, which enhance interleukin-2 transcription and induce stabilization of the mRNA, did not further increase the level of cytoplasmic HuR. Using an in vitro binding assay, we demonstrate that HuR binds the interleukin-2 mRNA and localize binding to a sequence downstream of the single nonameric AU-rich element that is present in its 3'-untranslated region. However, we conclude that HuR binding to the interleukin-2 mRNA, both in vitro and in vivo, is not associated with alterations in mRNA stability.

Received for publication, November 10, 2003 , and in revised form, January 28, 2004.

^* 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.

Supported in part by a grant from the Japanese Eye Bank Association.

^¶ To whom correspondence should be addressed: Bldg. 10, Rm. 10N112, 10 Center Dr. MSC-1857, Bethesda, MD 20892. Tel.: 301-435-4566; Fax: 301-480-1122; E-mail: jr50b{at}nih.gov.

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