Regulation of Apoptosis by Adenovirus E1A and E1B Oncogenes

Abstract

Adenovirus E1A promotes apoptosis by interacting with and inhibiting negative regulators of cell cycle control. Binding of E1A to, and inhibition of, the transcriptional coadaptor p300 promotes accumulation of the p53 tumor suppressor protein which induces apoptosis. By inhibiting p300, E1A prevents the transcriptional activation ofmdm-2,the product of which interacts with and promotes the degradation of p53. Thus the E1A–p300 interaction disables the negative feedback loop to control p53 levels, which left unrestrained, cause apoptosis rather than growth arrest. The E1B 19K protein functions analogously to Bcl-2 to inhibit apoptosis by E1A, p53, and multiple other stimuli. The E1B 19K protein functions by at least two independent mechanisms to inhibit apoptosis. First, the E1B 19K protein binds to the pro-apoptotic Bax protein to prevent loss of mitochondrial membrane potential, caspase activation, and apoptosis. Second, the E1B 19K protein inhibits caspase interaction by interfering with the function of adaptor molecules such as FADD and Ced-4 that interact with and activate caspases. By inhibiting FADD-dependent activation of the caspase FLICE, the E1B 19K protein can disable both the TNF-α- and the Fas-mediated death signaling pathways which play an important role in immune surveillance against virus infection and cancer. The E1B 19K protein binds to Ced-4, and presumably mammalian Ced-4 homologues, and thereby prevents caspase activation. Thus, the study of the mechanism of regulation of apoptosis by the adenovirus transforming proteins has revealed important regulatory steps in death signaling pathways.