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Journal of Virology, January 2008, p. 40-48, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01579-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Tumorigenic Adenovirus Type 12 E1A Inhibits Phosphorylation of NF-{kappa}B by PKAc, Causing Loss of DNA Binding and Transactivation{triangledown}

Hancheng Guan,1 Junfang Jiao,1 and Robert P. Ricciardi1,2*

Department of Microbiology, School of Dental Medicine,1 the Abramson Cancer Center, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191042

Received 6 June 2007/ Accepted 16 October 2007

Human adenovirus type 12 (Ad12) E1A protein (E1A-12) is the key determinant of viral tumorigenesis. E1A-12 mediates major histocompatibility complex class I (MHC-I) shutoff by inhibiting the DNA binding of the transcriptional activator NF-{kappa}B (p50/p65) to the class I enhancer. This enables Ad12 tumorigenic cells to avoid class I recognition and lysis by cytotoxic T lymphocytes. In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase A (PKAc) is essential for NF-{kappa}B DNA binding and transactivation activity. Treatment with H89 and knockdown of PKAc in cells led to the inhibition of phosphorylation at p50 Ser337 and p65 Ser276 and loss of DNA binding by NF-{kappa}B. Importantly, NF-{kappa}B phosphorylation by PKAc was repressed by tumorigenic E1A-12, but not by nontumorigenic Ad5 E1A (E1A-5). The stable introduction of E1A-12 into Ad5 nontumorigenic cells resulted in a decrease in the phosphorylation of NF-{kappa}B, loss of NF-{kappa}B DNA binding, and the failure of NF-{kappa}B to activate a target promoter, as well as diminution of MHC-I transcription and cell surface expression. Significantly, the amount and enzymatic activity of PKAc were not altered in Ad12 tumorigenic cells relative to its amount and activity in nontumorigenic Ad5 cells. These results demonstrate that E1A-12 specifically prevents NF-{kappa}B from being phosphorylated by PKAc.

* Corresponding author. Mailing address: University of Pennsylvania, Levy Research Building, Room 221, 4010 Locust Street, Philadelphia, PA 19104. Phone: (215) 898-3905. Fax: (215) 898-8385. E-mail: ricciardi{at}biochem.dental.upenn.edu

{triangledown} Published ahead of print on 24 October 2007.

Journal of Virology, January 2008, p. 40-48, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.01579-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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