Fig. 1: A time series showing cells expressing the HPV protein E2 (green) during the first growth phase (left, middle) and S phase (right) of the cell cycle. Degradation of E2 begins right before the S phase.
Reproduced from Ref. 1 © 2010 American Society for Microbiology
Determining how cervical cancer is induced could aid in the development of drugs to treat it. Now, a research team at the Institute of Medical Biology of A*STAR, Singapore, has found that the human papillomavirus (HPV) protein E2 can stabilize a cancer-causing, or ‘oncogenic’, protein within cells.
Infection of the epithelial cells of the cervix by HPV often leads to cervical cancer. To reduce the incidence of this disease, women are receiving vaccines that prevent HPV infection. Effective therapeutics, however, are still required.
Researchers in the field consider the protein Skp2 to be oncogenic because its expression is increased in many types of cancer, and it drives the cell cycle. When Sophie Bellanger and her co-workers expressed both Skp2 and the HPV protein E2 within epithelial cells in culture, they found elevated levels of Skp2 protein in the cells. Because the stabilization and accumulation of Skp2—driven by E2—could allow Skp2 to perform its oncogenic role in the epithelial cells, these findings provide an important link between HPV infection of the cervix and cervical cancer induction, Bellanger notes.
The researchers also found that Skp2 and E2 bound to each other when they expressed both in the cells. Skp2 is part of a protein complex that marks proteins for degradation. Bellanger suggests that this binding probably represents the Skp2 labeling of E2 for degradation, since reducing the expression of Skp2 in the epithelial cells extended the duration of E2’s presence in the cells. As E2 plays an important role in repressing the expression of the oncogenic HPV genes E6 and E7, the degradation of E2 by Skp2 could also drive tumor formation.
The team discovered that E2 degradation occurs immediately before the DNA synthesis phase, or ‘S’ phase, of the cell cycle (Fig. 1). Increased expression of Skp2 and of the HPV protein E7 have been shown previously to push cells into the S phase. This negative feedback loop in which E2 stabilizes Skp2, while Skp2 causes E2 degradation—and therefore the expression of E6 and E7—could be the first step of tumor formation in cervical cancer. As such, Bellanger and her co-workers may have revealed the mechanism that sets the cell cycle in motion in HPV-infected cervical epithelial cells.
“For the next step in this research,” says Bellanger, “we want to check whether E2 alone can transform epithelial cells in culture into tumor cells and understand the mechanisms involved.”
The A*STAR-affiliated authors in this highlight are from the Institute of Medical Biology.
