Adenoviruses—: Model Systems of Virus Replication, Human Cell Molecular Biology, and Neoplastic Transformation

ADENOVIRUSES—MODEL SYSTEMS OF VIRUS REPLICATION, HUMAN CELL MOLECULAR BIOLOGY, AND NEOPLASTIC TRANSFORMATION* MAURICE GREENf Introduction One ofthe greatchallenges facing us today, in my view, is to understand the molecular biology and functions ofthe human cell—how the synthesis (DNA replication) and expression (RNA transcription and translation ) of genes are regulated and how growth is controlled. Understanding human cell function may be prerequisite for the development of preventative and therapeutic measures to combat cancer and other chronic degenerative diseases and may help us to understand cell differentiation and why we age. For example, cancer is a disease ofcells—they have lost the ability to regulate their growth and to recognize the surface topography of other cells, leading them to grow in previously forbidden tissues of the body. To appreciate cancer at the cellular level, it is necessary to understand the regulatory functions that control cell growth. Until recently, the enormous complexity of eukaryotic cells seriously limited attempts to understand mammalian cell function; that is, it is almost impossible to pinpoint the critical events or gene products that are involved in neoplastic transformation. Oncogenic viruses are powerful tools for this study—they replicate in the nucleus of the host human cell using much of the host-cell machinery, and their genetic composition can be determined and virus-specific macromolecules can be easily identified within the cell. Most important, only one or a few viral gene *Taken from the Howard Taylor Ricketts Award Lecture, presented at the University of Chicago, May 24, 1976. tInstitute for Molecular Virology, St. Louis University School of Medicine, 3681 Park Avenue, St. Louis, Missouri 63110. I thank W. S. M. Wold for stimulating counsel in writing this article. The work in the author's laboratory was supported by grant AI-01725 from NIAID, Contract CP 43359 within the Virus Cancer Program of the NCI, and Research Career Award 5K6-AI-14739 from NIH. I welcome this opportunity to acknowledge the Virus Cancer Program of the NCI1 which through its funding and rapid communication of new information has contributed to remarkably rapid advances in our understanding of tumor viruses and eukaryotic cells in the past decade.© 1978 by The University of Chicago. 0031-5982/78/2103-0039$01.00 Perspectives in Biology and Medicine ¦ Spring 1978 \ 373 products are necessary to transform a cell to malignancy; a major research goal is to functionally characterize these viral-coded "transformation proteins" and to learn how they impart malignancy to a cell. Oncogenic viruses are of additional interest because they are major causes of cancer in animals and thus could be natural causes of cancer in man. Oncogenic viruses may have DNA or RNA as their genetic material. Of the known oncogenic DNA viruses, we have concentrated on the human adenoviruses (Ad), partly because they are very common human pathogens, but mainly because they provide extremely useful experimental systems for several important kinds of investigation, as will be described below. Over 80 distinct Ads have been isolated from a variety of animal species, including 31 human serotypes (Adl-31). The Ads were first isolated by Rowe, Huebner, and coworkers from adenoids in 1953 [1], the year of the discoveries of the double helix by Watson and Crick and the plaque assay for animal viruses by Dulbecco and Vogt. Thus, the births of adenovirology and modern molecular biology coincide , and the study of Ads encompasses an era of phenomenal growth in animal molecular virology. The human Ads are associated mainly with acute respiratory illness, often reaching epidemic proportions in military recruits. They infect most children before the age of five, can remain latent in the gastrointestinal tract and persist in lymphoid tissues, and can be isolated from 50-90 percent of surgically removed adenoids and tonsils placed in culture. The Ads have been associated with or isolated from patients with a variety ofdiseases, including ocular and gastrointestinal infections, rashes, and renal lesions. The Human Ads—Model Systems to Understand Virus Replication, Human Cell Molecular Biology, and Neoplastic Transformation The human Ads provide some of the best experimental systems for investigating oncogenic DNA-virus replication, cell transformation, and the molecular biology of human and transformed cells. The Ads replicate in the nucleus of...