Modulation of the Cell Division Cycle by Human Papillomavirus Type 18 E4

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Abstract
The life cycle of human papillomaviruses (HPVs) is tightly coupled to the differentiation program of their host epithelial cells. HPV E4 gene expression is first observed in the parabasal layers of squamous epithelia, suggesting that the E4 gene product contributes to the mechanism of differentiation-dependent virus replication, although its biological function remains unclear. We analyzed the effect of HPV type 18 E4 on cell proliferation and found that E4 expression induced cell cycle arrest at the G2/M boundary. The functional region of E4 necessary for the growth arrest activity was located in the central portion of the molecule, and this activity was independent of the E4-mediated collapse of cytokeratin intermediate filament structures.