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Journal of Virology, June 2006, p. 5349-5360, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02016-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Recombinant Adenoviral Vectors Can Induce Expression of p73 via the E4-orf6/7 Protein

Gary S. Shapiro,1,{dagger} Crystal Van Peursem,1,{ddagger} David A. Ornelles,2 Jerome Schaack,3 and James DeGregori1*

Department of Biochemistry and Molecular Genetics, Department of Pediatrics, Integrated Department of Immunology, Program in Molecular Biology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045,1 Department of Microbiology and Immunology, School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157,2 Department of Microbiology, Program in Molecular Biology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 800453

Received 21 September 2005/ Accepted 6 March 2006

Despite the utility of recombinant adenoviral vectors in basic research, their therapeutic promise remains unfulfilled. Most engineered adenoviral vectors use a heterologous promoter to transcribe a foreign gene. We show that adenoviruses containing the cytomegalovirus immediate-early promoter induce the expression of the proapoptotic cellular protein TAp73 via the cyclin-dependent kinase-retinoblastoma protein-E2F pathway in murine embryonic fibroblasts. Cells transduced with these vectors also expressed high levels of the adenoviral E4-orf6/7 and E2A proteins. By contrast, adenoviruses containing the ubiquitin C promoter failed to elicit these effects. E4-orf6/7 is necessary and sufficient for increased TAp73 expression, as shown by using retrovirus-mediated E4-orf6/7 expression and adenovirus with the E4-orf6/7 gene deleted. Activation of TAp73 likely occurs via E4-orf6/7-induced dimerization of E2F and subsequent binding to the inverted E2F-responsive elements within the TAp73 promoter. In addition, adenoviral vectors containing the cytomegalovirus immediate-early promoter, but not the ubiquitin C promoter, cooperated with chemotherapeutic agents to decrease cellularity in vitro. In contrast to murine embryonic fibroblasts, adenoviruses containing the ubiquitin C promoter, but not the cytomegalovirus immediate-early promoter, induced both E4-orf6/7 and TAp73 in human foreskin fibroblasts, emphasizing the importance of cellular context for promoter-dependent effects. Because TAp73 is important for the efficacy of chemotherapy, adenoviruses that increase TAp73 expression may enhance cancer therapies by promoting apoptosis. However, such adenoviruses may impair the long-term survival of transduced cells during gene replacement therapies. Our findings reveal previously unknown effects of foreign promoters in recombinant adenoviral vectors and suggest means to improve the utility of engineered adenoviruses by better controlling their impact on viral and cellular gene expression.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, Mail Stop 8101, P.O. Box 6511, Aurora, CO 80045. Phone: (303) 724-3230. Fax: (303) 724-3215. E-mail: james.degregori{at}uchsc.edu.

{dagger} Present address: Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA 92093.

{ddagger} Present address: Phosphosolutions, Colorado Bioscience Park, Aurora, CO 80010.

Journal of Virology, June 2006, p. 5349-5360, Vol. 80, No. 11
0022-538X/06/$08.00+0     doi:10.1128/JVI.02016-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.





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