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Molecular and Cellular Biology, May 2006, p. 3695-3706, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3695-3706.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tethering KSRP, a Decay-Promoting AU-Rich Element-Binding Protein, to mRNAs Elicits mRNA Decay

Chu-Fang Chou,1 Alok Mulky,2 Sushmit Maitra,1 Wei-Jye Lin,1 Roberto Gherzi,4 John Kappes,2,3 and Ching-Yi Chen1*

Department of Biochemistry & Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294,1 Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294,2 Birmingham Veterans Affairs, Medical Center Research Service, Birmingham, Alabama 35233,3 Gene Expression Regulation Laboratory, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy4

Received 11 January 2006/ Returned for modification 8 February 2006/ Accepted 27 February 2006

Inherently unstable mRNAs contain AU-rich elements (AREs) in their 3' untranslated regions that act as mRNA stability determinants by interacting with ARE-binding proteins (ARE-BPs). We have destabilized two mRNAs by fusing sequence-specific RNA-binding proteins to KSRP, a decay-promoting ARE-BP, in a tethering assay. These results support a model that KSRP recruits mRNA decay machinery/factors to elicit decay. The ability of tethered KSRP to elicit mRNA decay depends on functions of known mRNA decay enzymes. By targeting the Rev response element of human immunodeficiency virus type 1 by using Rev-KSRP fusion protein, we degraded viral mRNA, resulting in a dramatic reduction of viral replication. These results provide a foundation for the development of novel therapeutic strategies to inhibit specific gene expression in patients with acquired or hereditary diseases.

* Corresponding author. Mailing address: Department of Biochemistry & Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294. Phone: (205) 934-5073. Fax: (205) 975-2188. E-mail: cchen{at}uab.edu.

Molecular and Cellular Biology, May 2006, p. 3695-3706, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3695-3706.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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