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Regulation of the cell cycle and apoptosis by the oncogenes of adenovirus

Oncogene volume 20, pages 7836–7846 (2001)Cite this article

The oncogenes of adenovirus, E1A and E1B, play an essential role in establishing a productive virus infection in human cells, and are both necessary and sufficient for transformation of primary rodent epithelial cells (White, 1995, 1998). The products of the E1A and E1B genes also modulate the interaction between the infected cell and the immune system of the human or rodent host (Wold et al., 1999). E1A stimulates entry into S phase to create the appropriate environment for the replication of viral DNA in productively infected human cells. This same growth deregulatory function of E1A is also essential to the transformation of primary rodent cells. E1A accomplishes cell cycle deregulation by binding to and perturbing the normal function of key negative regulators of cell growth, including the retinoblastoma protein (Rb), and the transcriptional coactivator p300. Ironically, these very activities of E1A that are required for productive virus infection and oncogenic transformation also stimulate programmed cell death (apoptosis) (White, 1995, 1998). Apoptosis is the cellular defensive response to gross perturbation in cell growth regulation induced by E1A during virus infection and transformation. E1A expression in productively infected cells also decreases the threshold of killing by death signaling cytokines, such as tumor necrosis factor-alpha (TNF-α), which facilitates death of infected cells. Neither of these events is favorable for virus production. In transformation, the induction of apoptosis by E1A nearly abrogates the oncogenic activity of E1A, and necessitates that E1A be coexpressed with an inhibitor of apoptosis for transformation to occur. All of these pro-apoptotic activities are counteracted by expression of E1B, which sustains productive infection and transformation.

E1B encodes two proteins, E1B 55K and E1B 19K, which function in all or in part by inhibiting apoptosis (White, 1995, 1998). E1B 55K binds and inhibits the function of the p53 tumor suppressor protein, which has well-known roles in inhibiting cell cycle progression and stimulating apoptosis (Levine, 1997). E1B 19K is an anti-apoptotic adenoviral Bcl-2 homologue. Bcl-2 is the prototypical member of a family of proteins that regulate apoptosis (Gross et al., 1999). A gain-of-function in an anti-apoptotic Bcl-2 family member can promote cell survival and oncogenesis, whereas pro-apoptotic Bcl-2 family members are required for mediating apoptosis in development, and likely by tumor suppressor proteins in emerging cancer cells. The homology between E1B 19K and Bcl-2 includes direct sequence homology, functional interchangeability as apoptosis inhibitors, and interaction with some of the same intracellular proteins, implying a related biochemical function. E1B 19K blocks apoptosis induced by E1A in productive infection, by signaling from death ligands such as TNF-α, Fas ligand (FasL), and TRAIL emanating from an immune response, and by p53 in the transformation setting. Over the years we have been unraveling the molecular mechanisms by which E1A and E1B regulate cell proliferation and apoptosis in productive infection, in death receptor signaling, and by p53 in transformation. Much of what we have learned has direct parallels to the mechanisms by which normal human cells are converted to cancer cells. By defining these mechanisms we hope to provide novel avenues for therapeutic intervention in cancer treatment, and to have a better understanding of virus-host interactions.

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Acknowledgements

I wish to thank the members of the White laboratory Andrea Cuconati, Kurt Degenhardt, Holly Henry, Denise Perez, and Deirdre Nelson, Ramya Sundararajan, and Anju Thomas for comments and helpful discussions. This work was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute.

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  1. Howard Hughes Medical Institute, Rutgers University, Piscataway, NJ 08854, New Jersey, USA

    Eileen White

  2. Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ 08854, New Jersey, USA

    Eileen White

  3. Cancer Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, New Jersey, USA

    Eileen White

  4. Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, New Jersey, USA

    Eileen White

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White, E. Regulation of the cell cycle and apoptosis by the oncogenes of adenovirus. Oncogene 20, 7836–7846 (2001). https://doi.org/10.1038/sj.onc.1204861

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