Abrogation of the postmitotic checkpoint contributes to polyploidization in human papillomavirus E7-expressing cells.
High-risk types of human papillomavirus (HPV) are considered the major causative agents of cervical carcinoma. The transforming ability of HPV resides in the E6 and E7 oncogenes, yet the pathway to transformation is not well understood. Cells expressing the oncogene E7 from high-risk HPVs have a high incidence of polyploidy, which has been shown to occur as an early event in cervical carcinogenesis and predisposes the cells to aneuploidy. The mechanism through which E7 contributes to polyploidy is not known. It has been hypothesized that E7 induces polyploidy in response to mitotic stress by abrogating the mitotic spindle assembly checkpoint. It was also proposed that E7 may stimulate rereplication to induce polyploidy. We have tested these hypotheses by using human epithelial cells in which E7 expression induces a significant amount of polyploidy. We find that E7-expressing cells undergo normal mitoses with an intact spindle assembly checkpoint and that they are able to complete cytokinesis. Our results also exclude DNA rereplication as a major mechanism of polyploidization in E7-expressing cells upon microtubule disruption. Instead, we have shown that while normal cells arrest at the postmitotic checkpoint after adaptation to the spindle assembly checkpoint, E7-expressing cells replicate their DNA and propagate as polyploid cells. Thus, abrogation of the postmitotic checkpoint leads to polyploidy formation in E7-expressing human epithelial cells. Our results suggest that downregulation of pRb is important for E7 to induce polyploidy and abrogation of the postmitotic checkpoint.
Heilman
Susan A
SA
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nordberg
Joshua J
JJ
Liu
Yingwang
Y
Sluder
Greenfield
G
Chen
Jason J
JJ
D002455:Cell Division; D002478:Cells, Cultured; D006801:Humans; D015603:Keratinocytes / Q000821:virology*; D027383:Papillomaviridae / Q000254:growth & development*; D050725:Papillomavirus E7 Proteins / Q000096:biosynthesis*; D011123:Polyploidy
D050725:Papillomavirus E7 Proteins