Induction of chromosome abnormalities in mouse and human epidermal keratinocytes by the human papillomavirus type 16 E7 oncogene

Abstract

Cytogenetic abnormalities associated with human papillomavirus (HPV) type 16 were studied using primary human and mouse epidermal keratinocytes. The E7 transforming gene of HPV-16 was found to induce chromosome duplication in epidermal keratinocytes; little or no detectable chromosome disorganization was associated with the function of the E6 gene. These results suggest that the E7 gene-linked cytogenetic effect reflects HPV-16-associated pathogenicity in the early phase of transformation.

The human papillomavirus type 16 E6 and E7 oncoproteins cooperate to induce mitotic defects and genomic instability by uncoupling centrosome duplication from the cell division cycle

“…It has been shown that the integration of the viral genome into the host chromosome, a hallmark of malignant progression, may ref lect E6͞E7-mediated genomic instability (7). In keratinocytes but not in fibroblasts, expression of E7 was shown to induce aneuploidy (4,5), which is similar to what we observed in this study (Fig. 5).…”

“…The majority of these cancers contain HPV DNA integrated into the host cell genome and express only two viral genes, E6 and E7, both of which encode oncoproteins (1). Both HPV-immortalized cells and high-risk HPV-associated cervical neoplasias, including early precursor lesions, display genomic instability, which is absent in lesions caused by low-risk HPVs (2)(3)(4)(5)(6). Induction of genomic plasticity, therefore, constitutes an early and central event in HPV-associated carcinogenesis and may contribute to the integration of HPV DNA into the host genome (7).…”

Human papillomaviruses and centrosome duplication errors: modeling the origins of genomic instability

“…It is interesting to note that certain selection conditions provoke specific forms of chromosomal changes (Bardelli et al, 2001), however, these results are consistent with the model that expression of HPV-16 E7 reduces mitotic fidelity. Further support for this notion comes from the observation that rodent keratinocytes expressing the E7 oncoprotein showed a progressive loss of chromosomes with increased passage numbers whereas numerical imbalances were not detected in high-risk HPV E6 expressing cells (Hashida and Yasumoto, 1991). Recent results show that one mechanism by which HPV-16 E7 can undermine the mitotic machinery is the induction of abnormal centrosome numbers.…”

“…Chromosomal instability with gains and losses of whole chromosomes is a common finding in HPV immortalized cell lines (Hashida and Yasumoto, 1991;Solinas-Toldo et al, 1997). HPV-associated clinical lesions are aneuploid already at early, noninvasive stages (Bulten et al, 1998;Jones et al, 1967;Reid et al, 1984;Rihet et al, 1996;Steinbeck, 1997).…”

The human papillomavirus-16 E6 oncoprotein decreases the vigilance of mitotic checkpoints

“…SV40 large T antigen rapidly decreases ®delity of several mitotic checkpoints in normal human cells and a concomitant increased frequency of cytogenetic aberrations is observed (Chang et al, 1997). Expression of HPV-16 E6/E7 causes an increase in cytogenetic aberrations in normal human ®broblasts and both HPV-16 E6 and E7 are reported to induce such aberrations prior to immortalization in normal diploid human ®broblasts or keratinocytes (Hashida and Yasumoto, 1991;White et al, 1994).…”