Adenovirus transformation

Adenoviruses (Ad) were first isolated by Rowe and colleagues in 1953 followingthe culture of primary cells from human adenoids (Rowe et al. 1953). Virusspread within these cultures was evident by a characteristic cytopathic effectof rounded and clumped cells detaching from the plate. The following year,Hilleman and Werner observed a similar type of cytopathic effect in culturedcells exposed to respiratory secretions from Army recruit with acute respiratorydisease (Hilleman and Werner 1954). Common Ad infections are associatedwith pharyngitis, conjunctivitis and gastroenteritis. These infections are usuallyresolved quickly, resulting in lifelong immunity to the virus. Acute respiratorydisease is a more severe pneumonia-like infection most often found in themilitary which results in significant morbidity. The adenovirus family is largeand contains members that infect a wide range of animals, including monkeys,livestock, mice, birds, and humans. All these viruses consist of a naked icosahedralprotein shell (70-100 nm in diameter) that encapsidates a linear, doublestrandedDNA molecule.A major interest in studying Ad followed the discovery that Ad serotype 12(Ad12) caused malignant tumors in infected newborn hamsters (Trentin et al.1962). This seminal finding by Trentin and colleagues coincided with the discoveriesthat SV40 and polyomavirus also induce tumor formation in animalsin vivo and transformation in cultured cells in vitro and led to establishmentof the field of DNA tumor viruses. Fortunately, to date, there has been nosignificant evidence to implicate Ad in the development of human cancer. Theearly work in the study of Ad oncogenesis in vivo and Ad transformation invitro led to the conclusion that only members of Ad subgroup A (e.g., Ad12)caused tumors in animals, whereas Ad in subgroupAand other subgroups (e.g.,subgroup C, Ad2 and Ad5) were able to transform rodent cells in culture withcomparable efficiencies. More recent work has established that this reflects thespecific experimental conditions used in the analyses and that other Ad (e.g.,Ad9, subgroup D) are oncogenic in animal models.The focus of early work in the field of Ad oncogenesis was the identificationof viral proteins, mRNAs, and DNA sequences that are found in Ad-transformedcells and Ad-induced tumors (reviewed in Endter and Dobner 2004).The salient conclusions from these analyses include the observations that (1) AdDNA sequences from the genomic left-end 3,000-5,000 bp are both necessaryand sufficient to induce Ad transformation in vitro; (2) the same viral DNAsequences are found in Ad-induced tumors in vivo; (3) viral DNA sequences areintegrated into host chromosomal DNA in a relatively non-specific manner;and (4) specific viral mRNAs and proteins from Ad early regions 1A (E1A) and1B (E1B) are the major viral oncogenic determinants. More recent studies haveshown the involvement of viral proteins encoded by early region 4 (E4) in Ad9-induced tumors in vivo and in enhancing Ad5 transformation in vitro. Thisreview will focus on the roles of proteins encoded by E1A, E1B, and E4 in Adtransformation in vitro and oncogenesis in vivo, as well as distinctions betweendifferent Ad and their ability to cause cancer in animal models in vivo. Manyexcellent reviews on Ad transformation and oncogenesis have been published inthe past, and the reader is directed to the following specific articles to supplementthe material presented in this chapter (Berk 2005; Frisch and Mymryk2002; Tauber and Dobner 2001; Turnell and Mymryk 2006; White 2006).