p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy
Interdisciplinary Graduate Program
Program in Gene Function and Expression; Department of Medicine; Department of Obstetrics and Gynecology
Medical Subject Headings
DNA Replication; Human papillomavirus 16; Humans; Keratinocytes; Mitosis; Oncogene Proteins, Viral; Papillomavirus Infections; *Polyploidy; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Protein p53
Cancer Biology | Cell Biology | Life Sciences | Medicine and Health Sciences | Obstetrics and Gynecology
Polyploidy is often an early event during cervical carcinogenesis, and it predisposes cells to aneuploidy, which is thought to play a causal role in tumorigenesis. Cervical and anogenital cancers are induced by the high-risk types of human papillomavirus (HPV). The HPV E6 oncoprotein induces polyploidy in human keratinocytes, yet the mechanism is not known. It was believed that E6 induces polyploidy by abrogating the spindle checkpoint after mitotic stress. We have tested this hypothesis using human keratinocytes in which E6 expression induces a significant amount of polyploidy. We found that E6 expression does not affect the spindle checkpoint. Instead, we provide direct evidence that E6 is capable of abrogating the subsequent G(1) arrest after adaptation of the mitotic stress. E6 targets p53 for degradation, and previous studies have shown an important role for p53 in modulation of the G(1) arrest after mitotic stress. Importantly, we have discovered that E6 mutants defective in p53 degradation also induce polyploidy, although with lower efficiency. These results suggest that E6 is able to induce polyploidy via both p53-dependent and p53-independent mechanisms. Therefore, our studies highlight a novel function of HPV E6 that may contribute to HPV-induced carcinogenesis and improve our understanding of the onset of the disease.
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Citation: Cancer Res. 2007 Mar 15;67(6):2603-10. Link to article on publisher's site
Liu, Yingwang; Heilman, Susan Ann; Illanes, Diego; Sluder, Greenfield; and Chen, Jason J., "p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy" (2007). GSBS Student Publications. Paper 776.