Opposing oncogenic activities of small DNA tumor virus transforming proteins

Abstract

The E1A gene of species C human adenovirus is an intensely investigated model viral oncogene that immortalizes primary cells and mediates oncogenic cell transformation in cooperation with other viral or cellular oncogenes. Investigations using E1A proteins have illuminated important paradigms in cell proliferation and about the functions of cellular proteins such as the retinoblastoma protein. Studies with E1A have led to the unexpected discovery that E1A also suppresses cell transformation and oncogenesis. Here, I review our current understanding of the transforming and tumor-suppressive functions of E1A, and how E1A studies led to the discovery of a related tumor-suppressive function in benign human papillomaviruses. The potential role of these opposing functions in viral replication in epithelial cells is also discussed.

Figure 1

Schematic illustration of HAdv5 genome. The HAdv5 genome consists of a 35 kb linear double stranded DNA that is covalently linked to viral terminal proteins (TP) at the 3′ ends. The viral genome contains five early transcription units (E1A, E1B, E3, E4 and E2) and one major late transcription unit. The major late transcript is differentially processed into five groups of late mRNAs (L1–L5) to which three leader sequences are attached by RNA splicing. The late mRNAs code for various viral structural proteins. The left most 14% of the genome contains the E1A and E1B genes that constitute the transforming genes. l-E1A indicates the large E1A protein and s-E1A indicates the small E1A protein. The early region E4 of different HAdv species encodes multiple proteins and at least three of them, Orf 1, Orf 3 and Orf 6 (indicated by 1, 3 and 6) exhibit transforming activities.

Figure 2. Schematic illustration of interaction of cellular proteins with HAdv5 E1A proteins

The functional consequences of such protein interactions are also indicated. The N-terminal region of E1A exhibits a dominant oncogenic activity while the C-terminal region contributes suppression of oncogenesis. The green upward arrows indicate activation of various cellular processes and the red downward arrows indicate suppression of such processes.

Figure 3

Genome and proteins of HPV21. _[GT1] (a) Schematic illustration of HPV21 genome. The genome structures of beta-HPVs conform to the overall genome structures of alpha-HPVs except that beta-HPVs do not encode an early protein, E5. The genome of HPV21 consists of 7.9 kb circular double stranded DNA. The viral genome encode five early proteins (designated as E1, E2, E4, E6 and E7) and two late proteins (designated as L1 and L2) that are viral capsid proteins. The viral genome contains a non-coding region (NCR) that contains the major promoter for the transcription of early genes. The early genes E6 and E7 constitute the transforming genes. (b) Schematic illustration of the E6 proteins of EV-associated beta-HPVs. The unique N-terminal domains of the E6 proteins of HPV14, HPV21 and HPV20 are compared with the FOXK1/K2-interacting motif of HAdv5 E1A in the boxed area._[GT2]

Figure 4

Potential consequences of epithelial differentiation on virus multiplication. The activities of the E1A N-terminal region are depicted promoting cell proliferation, viral DNA replication and possibly _[GT3] epithelial to mesenchymal cell transformation. The activities of the E1A C-terminal region are depicted as possibly _[GT4] promoting mesenchymal to epithelial transformation thereby providing a cellular environment that facilitates further steps in virus multiplication.