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J. Biol. Chem., Vol. 282, Issue 11, 8317-8324, March 16, 2007

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Epstein-Barr Virus Lytic Infection Induces Retinoic Acid-responsive Genes through Induction of a Retinol-metabolizing Enzyme, DHRS9^*

Richard J. Jones, Sarah Dickerson, Prassana M. Bhende, Henri-Jacque Delecluse^¶, and Shannon C. Kenney¹

From the Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27514, the ^¶German Cancer Research Center, Postfach 101949, 69009 Heidelberg, Germany, and the Departments of Medicine and Oncology, McArdle Laboratory, University of Wisconsin, Madison, Wisconsin 53706

Lytic Epstein-Barr virus (EBV) replication occurs in differentiated, but not undifferentiated, epithelial cells. Retinoic acid (RA) induces epithelial cell differentiation. The conversion of retinol into its active form, retinoic acid, requires retinol dehydrogenase enzymes. Here we show that AGS gastric carcinoma cells containing the lytic form of EBV infection have enhanced expression of a gene (DHRS9) encoding an enzyme that mediates conversion of retinol into RA. DHRS9 expression is also increased following induction of lytic viral infection in EBV-positive Burkitt lymphoma cells. We demonstrate that the EBV immediate-early protein, BZLF1, activates the DHRS9 promoter through a direct DNA binding mechanism. Furthermore, BZLF1 expression in AGS cells is sufficient to activate DHRS9 gene expression and increases the ability of retinol to induce the RA-responsive gene, CYP26A1. Production of RA during the lytic form of EBV infection may enhance viral replication by promoting keratinocyte differentiation.

Received for publication, September 7, 2006 , and in revised form, January 22, 2007.

^* This work was supported by Public Health Service Grants P01-CA19014, R01-CA66519, and R01-CA58853 (to S. C. K.) from the NCI/National Institutes of Health. 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.

¹ To whom correspondence should be addressed: Rm. 421A, McArdle Laboratory, 1400 University Ave., Madison, WI 53706. Tel.: 608-261-1196; Fax: 608-262-2824; E-mail: skenney{at}wisc.edu.

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