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Journal of Virology, September 2005, p. 11105-11114, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11105-11114.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Down-Regulation of p53 by Double-Stranded RNA Modulates the Antiviral Response

Joao T. Marques,1 Dominique Rebouillat,1 Chilakamarti V. Ramana,3 Junko Murakami,1,4 Jason E. Hill,2 Andrei Gudkov,2 Robert H. Silverman,1 George R. Stark,2 and Bryan R. G. Williams1*

Departments of Cancer Biology,1 Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195,2 Department of Medicine, Yale University, New Haven, Connecticut 06516,3 Department of Obstetrics and Gynecology, Mazda Hospital, 2-15 Aosakiminami, Fuchu-cho, Aki-gun Hiroshima, 735-8585, Japan4

Received 25 March 2005/ Accepted 25 May 2005

p53 has been well characterized as a tumor suppressor gene, but its role in antiviral defense remains unclear. A recent report has demonstrated that p53 can be induced by interferons and is activated after vesicular stomatitis virus (VSV) infection. We observed that different nononcogenic viruses, including encephalomyocarditis virus (EMCV) and human parainfluenza virus type 3 (HPIV3), induced down-regulation of p53 in infected cells. Double-stranded RNA (dsRNA) and a mutant vaccinia virus lacking the dsRNA binding protein E3L can also induce this effect, indicating that dsRNA formed during viral infection is likely the trigger for down-regulation of p53. The mechanism of down-regulation of p53 by dsRNA relies on translation inhibition mediated by the PKR and RNase L pathways. In the absence of p53, the replication of both EMCV and HPIV3 was retarded, whereas, conversely, VSV replication was enhanced. Cell cycle analysis indicated that wild-type (WT) but not p53 knockout (KO) fibroblasts undergo an early-G1 arrest following dsRNA treatment. Moreover, in WT cells the onset of dsRNA-induced apoptosis begins after p53 levels are down-regulated, whereas p53 KO cells, which lack the early-G1 arrest, rapidly undergo apoptosis. Hence, our data suggest that the down-regulation of p53 facilitates apoptosis, thereby limiting viral replication.

* Corresponding author. Mailing address: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Phone: (216) 445-9652. Fax: (216) 445-6269. E-mail: williab{at}ccf.org.

Journal of Virology, September 2005, p. 11105-11114, Vol. 79, No. 17
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.17.11105-11114.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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