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Journal of Virology, April 1999, p. 3071-3079, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Early Region 1 Transforming Functions Are Dispensable for Mammary Tumorigenesis by Human Adenovirus Type 9

Darby L. Thomas,1,2 Sook Shin,2,dagger Bernard H. Jiang,3,Dagger Hannes Vogel,4 Margery A. Ross,3,§ Michael Kaplitt,3,parallel Thomas E. Shenk,3 and Ronald T. Javier2,*

Program in Cell and Molecular Biology,1 Division of Molecular Virology,2 and Department of Pathology,4 Baylor College of Medicine, Houston, Texas 77030, and Department of Molecular Biology, Howard Hughes Medical Institute, Princeton University, Princeton, New Jersey 085443

Received 3 December 1998/Accepted 4 January 1999

Some human adenoviruses are tumorigenic in rodents. Subgroup A and B human adenoviruses generally induce sarcomas in both male and female animals, and the gene products encoded within viral early region 1 (E1 region) are both necessary and sufficient for this tumorigenicity. In contrast, subgroup D human adenovirus type 9 (Ad9) induces estrogen-dependent mammary tumors in female rats and requires the E4 region-encoded ORF1 oncoprotein for its tumorigenicity. Considering the established importance of the viral E1 region for tumorigenesis by adenoviruses, we investigated whether this viral transcription unit is also necessary for Ad9 to generate mammary tumors. The nucleotide sequence of the Ad9 E1 region indicated that the gene organization and predicted E1A and E1B polypeptides of Ad9 are closely related to those of other human adenovirus E1 regions. In addition, an Ad9 E1 region plasmid demonstrated focus-forming activity in both low-passage-number and established rat embryo fibroblasts, whereas a large deletion within either the E1A or E1B gene of this plasmid diminished transforming activity. Surprisingly, we found that introducing the same transformation-inactivating E1A and E1B deletions into Ad9 results in mutant viruses that retain the ability to elicit mammary tumors in rats. These results are novel in showing that Ad9 represents a unique oncogenic adenovirus in which the E4 region, rather than the E1 region, encodes the major oncogenic determinant in the rat.

* Corresponding author. Mailing address: Division of Molecular Virology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-3898. Fax: (713) 798-3586. E-mail: rjavier{at}bcm.tmc.edu.

dagger Present address: Department of Genetics, The Salk Institute, La Jolla, CA 92037.

Dagger Present address: St. Joseph Mercy Hospital, Ann Arbor, MI 48106.

§ Present address: Department of Biochemistry, University of Connecticut Health Center, Farmington, CT 06032.

parallel Present address: Department of Neurosurgery, New York Hospital-Cornell University Medical College, New York, NY 10021.

Journal of Virology, April 1999, p. 3071-3079, Vol. 73, No. 4
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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