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J. Biol. Chem., Vol. 278, Issue 40, 38325-38332, October 3, 2003

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A Novel Role for RAX, the Cellular Activator of PKR, in Synergistically Stimulating SV40 Large T Antigen-dependent Gene Expression^*

Mingli Yang, Takahiko Ito  and W. Stratford May 

From the University of Florida Shands Cancer Center and Department of Medicine, University of Florida, Gainesville, Florida 32610-0232

The double-stranded (ds) RNA-binding protein RAX was discovered as a stress-induced cellular activator of the dsRNA-dependent protein kinase (PKR), a key regulator of protein synthesis in response to viral infection and cellular stress. We now report a novel function of RAX, independent of PKR, to enhance SV40 promoter (origin)/enhancer-dependent gene expression. Several mammalian cell lines including COS-7, CV-1, and HeLa cells were tested. Results reveal that the SV40 large T antigen is required for RAX-mediated, synergistic enhancement of gene expression. RAX augments SV40 regulatory element-dependent DNA replication and transcription. The mechanism requires the SV40 enhancer, a viral transcriptional element that is necessary for efficient SV40 DNA replication in vivo. Mutational analysis reveals that the dsRNA-binding domains of RAX are required for the gene expression enhancing function. Thus, in addition to stimulating PKR activity, RAX can positively regulate both SV40 large T antigen-dependent DNA replication and transcription in a mechanism that may alter the interaction of the cellular factor(s) with the SV40 enhancer via the dsRNA-binding domains of RAX. This novel function of RAX may have implications for regulation of mammalian DNA replication and transcription because of the many similarities between the viral and cellular processes.

Received for publication, April 2, 2003 , and in revised form, June 30, 2003.

^* This work was supported by National Institutes of Health Grant HL54083. 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.

Present address: Gifu Social Insurance Hospital, 1221-5 Dota, Kani, Gifu 509-0206, Japan.

To whom correspondence should be addressed: University of Florida Shands Cancer Center, P.O. Box 100232, 1600 S.W. Archer Rd., Gainesville, FL 32610-0232. Tel.: 352-846-1145; Fax: 352-846-1193; E-mail: smay{at}ufscc.ufl.edu.

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				R. L. Bennett, W. L. Blalock, and W. S. May Serine 18 Phosphorylation of RAX, the PKR Activator, Is Required for PKR Activation and Consequent Translation Inhibition J. Biol. Chem., October 8, 2004; 279(41): 42687 - 42693. [Abstract] [Full Text] [PDF]