Regulation of Apoptosis by the Transforming Genes of the DNA Tumor Virus Adenovirus

Abstract

The human DNA tumor virus adenovirus encodes two transforming genes, the E1A and E1B oncogenes, which cooperate to oncogenically transform primary rodent cells. The E1A products efficiently stimulate cell proliferation, but fail to transform cells due to the induction of programmed cell death (apoptosis). Expression of either the E1B oncogene, or the human bcl-2 proto-oncogene, blocks E1A-associated apoptosis to produce transformation with high frequency. Thus, induction of proliferation by E1A must be coupled to suppression of an intrinsic cell suicide pathway for the efficient transformation of primary cells.

The E1B oncogene encodes the unique 19-kDa and 55-kDa proteins, both of which independently suppress apoptosis and greatly enhance transformation by E1A. Suppression of apoptosis by the E1B 19-kDa protein is required not only in transformation of rodent cells with E1A, but also in adenovirus-infected human cells, where it sustains cell viability to maximize virus production. The E1B 19-kDa protein has the additional ability to block apoptosis induced by tumor necrosis factor (TNF)-α, and anti-Fas antibodies, potentially contributing to escape from antiviral and anticancer immune surveillance.

What E1A does to trigger apoptosis and the mechanism utilized by E1B 19-kDa and 55-kDa proteins and Bcl-2 to suppress apoptosis is of fundamental importance to understand how programmed cell death is regulated. It is now clear that the p53 tumor suppressor gene product mediates apoptosis by E1A, and that the E1B gene encodes independent, overlapping functions to disable p53-mediated apoptosis. The E1B 55-kDa protein binds to and inhibits p53 directly, but the mechanism by which the 19-kDa protein interferes with p53 function is not yet known.

In this review, I will discuss the means by which these conclusions were derived and how the transforming genes of adenovirus can be utilized to ascertain the molecular basis by which apoptosis is regulated.