Adenovirus early E4 genes in viral oncogenesis

Abstract

Previous investigations into potential transforming activities of adenovirus (Ad) early genes were largely overshadowed by the more obvious roles of E1A and E1B products. One exception was an Ad9 E4 protein (ORF1) shown to enhance transformation of cultured cells and promote mammary tumors in female rats. Recently, signi®cant advances in understanding Ad E4 gene products at the molecular level have revealed that these proteins possess an unexpectedly diverse collection of functions, which not only orchestrate many viral processes, but overlap with oncogenic transformation of primary mammalian cells. Operating through a complex network of protein interactions with key viral and cellular regulatory components, Ad E4 products are apparently involved in transcription, apoptosis, cell cycle control, DNA repair, cell signaling, posttranslational modi®cations and the integrity of nuclear multiprotein complexes known as PML oncogenic domains (PODs). Some of these functions directly relate to known transforming and oncogenic processes, or implicate mechanisms such as modulating the function and subcellular localization of cellular PDZ domain-containing proteins, POD reorganization, targeted proteolytic degradation, inhibition of DNA double-strand break repair and`hit-and-run' mutagenesis. Here, we summarize the recent data and discuss how E4 gene product interactions may contribute to viral oncogenesis. Oncogene (2001) 20, 7847 ± 7854.

Inactivating intracellular antiviral responses during adenovirus infection

“…Adenovirus expresses genes that achieve these same changes in the course of a productive infection. For example, the E1a (Frisch and Mymryk, 2002) and E4 proteins (Tauber and Dobner, 2001a) promote cellular proliferation, the E4 proteins potentiate growth signals transmitted through the PI3-kinase pathway (Frese et al, 2003;O'Shea et al, 2005), the E1b proteins block apoptosis (Cuconati and White, 2002) and the E4 proteins dismantle the cellular DNA damage response (Stracker et al, 2002;Carson et al, 2003). In addition, the E3 proteins as well as interactions among E1a, E1b and E2 proteins blunt the response to proinflammatory and death-inducing signals (McNees and Gooding, 2002;Fessler et al, 2004;Schaack, 2005).…”

Relocalization of the Mre11-Rad50-Nbs1 Complex by the Adenovirus E4 ORF3 Protein Is Required for Viral Replication

“…E4 ORF3 and E4 ORF6 have compensatory functions to stimulate efficient viral DNA replication independently of one another (4,15). E4 ORF3 and E4 ORF6 proteins both bind to the E1B 55-kDa protein and play roles in the regulation of late virus RNA transcription and splicing, inhibition of Ad genome concatenation, and stimulation of viral growth (28).…”

Antitumor efficacy and tumor-selective replication with a single intravenous injection of OAS403, an oncolytic adenovirus dependent on two prevalent alterations in human cancer

“…15,16 Ad E4 encodes genes that potentiate a variety of adenoviral functions that influence cell toxicity and host immune responses and are required for viral replication. 15,17 Owing to their essential importance, tumorselective transcriptional control of these genes may offer an additional advantage. Replacing the native E4 promoter with a heterologous tumor-selective promoter is expected to augment tumor-selective control.…”