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Journal of Virology, August 2008, p. 8105-8111, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00536-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vivo Potential Effects of Adenovirus Type 5 E1A and E1B on Lung Carcinogenesis and Lymphoproliferative Inflammation{triangledown}

Yongping Yang,1,2*,{dagger} Colin McKerlie,3,4,5,{dagger} Zhan Lu,2 Lena Wang,1 and Manuel Buchwald2,6

Center for Cancer Research, NCI, Frederick, Maryland,1 Genetics and Genomic Biology Programs, Hospital for Sick Children,2 Cancer Biology Program, Sunnybrook and Women's College Health Science Centre,3 Departments of Immunology,4 Pathobiology,5 Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada6

Received 10 March 2008/ Accepted 23 May 2008

Triggering uncontrolled cellular proliferation, chronic inflammation, and/or disruption of p53 activity is critical for tumorigenesis initiated by latent viral oncogenes. The adenovirus type 5 (Ad5) early genes E1A and E1B can maintain lifelong latency in the lungs of patients with chronic pulmonary diseases. To determine the in vivo effects of the latent Ad5 E1A and E1B oncogenes, we have examined the influence of Ad5 E1A and E1B gene products on mouse lung carcinogenesis and inflammation by generation and characterization of lung-specific transgenic mouse models. Here, we show that either the Ad5 E1A 243-amino-acid (aa) protein or the E1B 58-kDa protein was dominantly expressed in the transgenic lung. Preferential expression of Ad5 E1A 243-aa protein alone was not sufficient to induce lung carcinogenesis but resulted in low-grade cellular proliferation and high-grade lymphoproliferative inflammation in the lung. The presence of Ad5 E1B dramatically enhanced the expression of the E1A 243-aa protein, in addition to impairing p53 and apoptosis response, resulting in uncontrolled cellular proliferation, lymphoproliferative inflammation, and metastatic carcinomas in the lung after a period of latency. Our studies may provide clues to understanding the potential in vivo biological effects of Ad5 E1A and E1B latent in the lung and a new scope for assessing in vivo functions of viral genes latent in the infection target tissue.

* Corresponding author. Mailing address: Biopharmaceutical Development Program, NCI-Frederick, Frederick, MD 21702. Phone: (301) 846-5135. Fax: (301) 846-6228. E-mail: yongpiny{at}mail.nih.gov

{triangledown} Published ahead of print on 4 June 2008.

{dagger} Y.Y. and C.M. are equal first authors.

Journal of Virology, August 2008, p. 8105-8111, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00536-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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