Almost famous: Human adenoviruses (and what they have taught us about cancer)

Abstract

Papillomaviruses, polyomaviruses and adenoviruses are collectively categorized as the small DNA tumour viruses. Notably, human adenoviruses were the first human viruses demonstrated to be able to cause cancer, albeit in non-human animal models. Despite their long history, no human adenovirus is a known causative agent of human cancers, unlike a subset of their more famous cousins, including human papillomaviruses and human Merkel cell polyomavirus. Nevertheless, seminal research using human adenoviruses has been highly informative in understanding the basics of cell cycle control, gene expression, apoptosis and cell differentiation. This review highlights the contributions of human adenovirus research in advancing our knowledge of the molecular basis of cancer.

Keywords: E1A; E1B; E4; Hallmarks of cancer; Human adenovirus; Transformation.

Fig. 1

HAdV-C5 genome organization with highlighted E1A, E1B, and E4 genes. The human adenovirus (HAdV)-C5 genome, shown in blue, is approximately 36 kb of linear double-stranded DNA. Although Fig. 1 depicts the HAdV-C5 genome, all known HAdV genomes are similarly organized. However, some individual open reading frames (ORFs) may be present or absent in any given HAdV species. The viral genome is flanked by inverted terminal repeats (grey) on both strands, with the 5′ end covalently bound to the viral terminal protein (TP). Early genes E1A, E1B, E2A, E2B, E3 and E4 are shown as green arrows and are expressed prior to the onset of viral genome replication. Late genes L1-5 and μ are shown as red arrows and are expressed following the onset of viral genome replication. Intermediate early genes pIX and pVIa2, as well as the viral-associated (VA) RNAs are shown as yellow arrows. E1A, E1B and E4 genes have oncogenic properties and have been selected for more detailed description. E1A: The E1A primary transcript contains two exons separated by an intron which is spliced out for the 13S/289R E1A isoform. Exon 1 contains a unique region that is present in the 13S/289R E1A isoform, but is spliced out in the 12S/243R E1A isoform. The protein products of both major E1A isoforms contain conserved regions (CR)1, 2 and 4, while CR3 is unique to 13S/289R. Only the E1A primary transcript and two major isoforms are shown for simplicity. E1B: The E1B 22S transcript contains an exon, intron, and 3′ UTR. E1B 19K/176R is translated from the start of exon 1 and spliced in the middle of the exon to the 3′ UTR. E1B 55K/496R is translated starting from an internal translation initiation site and spliced at the intron to the 3′ UTR. Only the E1B 22S transcript and two major isoforms are shown. E4: The E4 gene and all seven major E4 protein products are shown. E4 contains multiple ORFs that encode for the following seven proteins: E4orf1, E4orf2, E4orf3, E4orf4, E4orf3/4, E4orf6 and E4orf6/7. Created with BioRender.com. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Protein interaction map of HAdV oncoproteins E1A, E1B and E4 and their connection to the hallmarks of cancer. Based on their relevance to the hallmarks of cancer, selected protein-protein interactions for E1A, E1B and E4 (including their isoforms) were visualized using Cytoscape [324]. Proteins shaded with light purple indicated a cellular target is shared by more than one of the HAdV proteins described in this review. Cancer-relevant cellular targets of each viral protein were identified from the literature and imported from the STRING database into Cytoscape. Interactions between cellular proteins were filtered to include only those with experimental evidence and high STRING confidence scores (>0.7). Targets of each viral protein have been colour coded according to their association with each respective hallmark of cancer. Importantly, each cellular target has a potential relevance to various hallmarks of cancer, even though their role in HAdV-mediated transformation may be unknown. Although an integrated analysis of E1A, E1B and E4 has yet to been performed, visualizing their interactions in this way demonstrates substantial overlap within the underlying interaction map. Notably, several cellular proteins, highlighted in purple, are targeted by multiple different viral proteins, suggesting potential synergy or antagonism on their function. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)