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Journal of Virology, December 1999, p. 10095-10103, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Induction of Transformation and p53-Dependent Apoptosis by Adenovirus Type 5 E4orf6/7 cDNA

Shigeru Yamano,1,2 Takashi Tokino,1 Motoaki Yasuda,1,2 Masanori Kaneuchi,1 Minoru Takahashi,3 Yoshiro Niitsu,3 Kei Fujinaga,1,dagger and Toshiharu Yamashita1,*

Department of Molecular Biology, Cancer Research Institute1 and Fourth Department of Internal Medicine,3 Sapporo Medical University School of Medicine, Chuo-ku, and Department of Dental Radiology, School of Dentistry, Hokkaido University, Kita-ku, Sapporo 060, Japan2

Received 26 October 1998/Accepted 31 August 1999

Adenovirus (Ad) E4orf6/7, one of the early gene products of human Ads, forms a stable complex with the cellular transcription factor E2F to activate transcription from the Ad E2 promoter. E2F cDNAs have growth-promoting and apoptosis-inducing activities when overexpressed in cells. We cloned Ad5 E4orf6/7 cDNA in both simian virus 40- and human cytomegalovirus-based expression vectors to examine its transforming and apoptotic activities. The cloned E4orf6/7 collaborated with a retinoblastoma protein (RB)-nonbinding and therefore E2F-nonreleasing mutant of Ad5 E1A (dl922/947) to morphologically transform primary rat cells, suggesting that E2F is an important cellular protein functioning downstream of E1A for transformation. In a G418 colony formation assay, E4orf6/7 was shown to suppress growth of untransformed rat cells. Moreover, a recombinant Ad expressing Ad5 E4orf6/7 induced apoptosis in rat cells when coinfected with wild-type p53-expressing Ad. Mutational analysis of E4orf6/7 revealed that both of the domains required for growth inhibition and transformation by E4orf6/7 lay in the C-terminal region, which is essential for transactivation from the upstream sequence of an E2a promoter containing E2F-binding sites. However, the smallest mutant of E4orf6/7, encoding the C-terminal 59 amino acids, failed to complement the RB-nonbinding dl922/947 mutant despite showing growth inhibition and E2F transactivation activities. Thus, it is suggested that a subregion of E4orf6/7 which is required for growth inhibition and transformation in collaboration with dl922/947 overlaps the transactivation domain of E4orf6/7.

* Corresponding author. Mailing address: Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University School of Medicine, South 1, West 17, Chuo-ku, Sapporo 060, Japan. Phone: 81-11-611-2111. Fax: 81-11-618-3313. E-mail: yamasita{at}sapmed.ac.jp.

dagger Present address: Biotechnology Research Laboratories, Takara Shuzo Co., Ltd., Noji, Kusatsu, Shiga 525, Japan.

Journal of Virology, December 1999, p. 10095-10103, Vol. 73, No. 12
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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