The human papillomavirus type 16 E6 oncogene induces premature mitotic chromosome segregation

Plug-Demaggio, Annemieke W; McDougall, James K.

doi:10.1038/sj.onc.1205903

Cited by 17 publications

(17 citation statements)

References 28 publications

(21 reference statements)

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“…Both numerical and structural chromosomal abnormalities are a frequent feature of HPV oncoprotein expressing cells; and the expression of both E6 and E7 proteins induce mitotic abnormalities in keratinocytes [31, 33]. If, as our data indicate, the loss of the PDZ binding function of E6 causes an increase in abnormal cells in anaphase and telophase, and elevated levels of micronuclei formation, then this would lead to an increase in the frequency of chromosomal abnormalities.…”

Section: Resultsmentioning

confidence: 70%

Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein

et al. 2017

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The function of a conserved PDS95/DLG1/ZO1 (PDZ) binding motif (E6 PBM) at the C-termini of E6 oncoproteins of high-risk human papillomavirus (HPV) types contributes to the development of HPV-associated malignancies. Here, using a primary human keratinocyte-based model of the high-risk HPV18 life cycle, we identify a novel link between the E6 PBM and mitotic stability. In cultures containing a mutant genome in which the E6 PBM was deleted there was an increase in the frequency of abnormal mitoses, including multinucleation, compared to cells harboring the wild type HPV18 genome. The loss of the E6 PBM was associated with a significant increase in the frequency of mitotic spindle defects associated with anaphase and telophase. Furthermore, cells carrying this mutant genome had increased chromosome segregation defects and they also exhibited greater levels of genomic instability, as shown by an elevated level of centromere-positive micronuclei. In wild type HPV18 genome-containing organotypic cultures, the majority of mitotic cells reside in the suprabasal layers, in keeping with the hyperplastic morphology of the structures. However, in mutant genome-containing structures a greater proportion of mitotic cells were retained in the basal layer, which were often of undefined polarity, thus correlating with their reduced thickness. We conclude that the ability of E6 to target cellular PDZ proteins plays a critical role in maintaining mitotic stability of HPV infected cells, ensuring stable episome persistence and vegetative amplification.

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Section: Resultsmentioning

confidence: 70%

Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein

et al. 2017

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“…This is biologically relevant since in HPV-infected cells, E6 could potentially trigger the spindle checkpoint as it induces a high percentage of metaphase-lagging (misaligned) chromosomes (5,28). After treatment with nocodazole, E7-expressing PHKs and RPE1 cells showed a significant increase in polyploidy compared to vector controls (42.9% versus 10.0% in PHKs and 42.0% versus 1.0% in RPE1 cells; Fig.…”

Section: Expression Of Hpv E7 Results In Polyploidymentioning

confidence: 95%

Abrogation of the Postmitotic Checkpoint Contributes to Polyploidization in Human Papillomavirus E7-Expressing Cells

Heilman

Nordberg

Liu³

et al. 2009

J Virol

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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.An important hallmark of human cancers is aneuploidy, the state in which a cell has extra or missing chromosomes (12,25). Polyploidy is the state in which cells have more than two equal sets of chromosomes and is thought to be an early event in multistep carcinogenesis that can lead to aneuploidy (1, 24), as exemplified in Barrett's esophagus (11). Polyploidy has recently been shown to occur as an early event in cervical carcinogenesis and to predispose the cells to aneuploidy (26). Other recent studies have shown that tetraploid but not diploid mouse or human cells induce tumor formation in mice (3, 9). These studies highlight the potential importance of polyploidy in carcinogenesis.The cellular mechanisms responsible for this polyploidy formation are as of yet undetermined, but several models have been proposed. First, abrogation of the spindle assembly checkpoint followed by cleavage failure may lead to polyploidy formation (36,40). A second proposed model is rereplication, a process of multiple rounds of DNA replication without an intervening mitosis. Third, cells that adapt to the mitotic spindle checkpoint halt in a G 1 -like state with 4C DNA content. Abrogation of this postmitotic checkpoint allows the cells to replicate their 4C DNA content, leading to polyploidy formation. This has been shown in cells that express the human papillomavirus type 16 (HPV-16) E6 oncogene that degrades p53 (21). Finally, cleavage failure, which yiel...

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“…, protein phosphatase 2A and p300 (Duensing and Munger, 2002;Davies et al, 2003), which leads to high genetic instability in the immortalized cells (Bernues et al, 1991;Ouellette et al, 2000;Duensing and Munger, 2002;Iftner et al, 2002;Plug-Demaggio and McDougall, 2002;Davies et al, 2003;Liu et al, 2004). In contrast, our immortal cell line (T137pRbi) showed that little genetic instability had been induced by the disruption of pRb pathway and ectopic expression of hTERT (Table 1).…”

Section: Ink4amentioning

confidence: 61%

Disruption of the retinoblastoma pathway by small interfering RNA and ectopic expression of the catalytic subunit of telomerase lead to immortalization of human ovarian surface epithelial cells

et al. 2006

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The risk of developing ovarian cancer is about 1% over a lifetime, but it is the most deadly gynecologic cancer, in part due to lack of diagnostic markers for early-stage disease and cell model system for studying early neoplastic changes. Most existing immortal human ovarian surface epithelial cells were achieved by using viral protein such as SV40 T/t antigen or E6/E7, which inactivate multiple cellular pathways. In the current study, we used a small interfering RNA (siRNA) against the retinoblastoma gene (pRb) and ectopic expression of human telomerase reverse transcriptase (hTERT) to immortalize the primary ovarian epithelial cell line OSE137 and two additional human ovarian surface epithelial cells. The immortalized OSE137 showed increased telomerase activity, lengthened telomeres, increased G 2 /M phase, altered cell-cycle regulatory proteins but nontumorigenic. As both Rb and hTERT pathways are commonly altered in human ovarian cancer and these genetic changes are faithfully modeled in these cells without using viral protein, these immortal cells represent an authentic in vitro model system with which to study the initiation and progression of human ovarian cancer.

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The human papillomavirus type 16 E6 oncogene induces premature mitotic chromosome segregation

Cited by 17 publications

References 28 publications

Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein

Mitotic control of human papillomavirus genome-containing cells is regulated by the function of the PDZ-binding motif of the E6 oncoprotein

Abrogation of the Postmitotic Checkpoint Contributes to Polyploidization in Human Papillomavirus E7-Expressing Cells

Disruption of the retinoblastoma pathway by small interfering RNA and ectopic expression of the catalytic subunit of telomerase lead to immortalization of human ovarian surface epithelial cells

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