Human Papillomavirus E7 Oncoproteins Bind a Single Form of Cyclin E in a Complex with cdk2 and p107

Mcintyre, Maritza C.; Ruesch, Margaret N.; Laimins, Laimonis A.

doi:10.1006/viro.1996.0008

Cited by 134 publications

(97 citation statements)

References 5 publications

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“…In addition our ®ndings suggest that this might be relevant for the ability of HPV16 E7 to transform cells. This is supported by our ®ndings that MPP2 can stimulate E7/Ha-Ras-induced colonies in REFs and that neither HPV6 E7 nor HPV16 E7 mutants impaired in transformation (Phelps et al, 1992;McIntyre et al, 1996) were able to stimulate MPP2-speci®c transactivation (Figures 6, 8 and 9). Importantly the chromosomal localization of MPP2 was recently mapped to 12p13 (Korver et al, 1997b).…”

Section: Discussionsupporting

confidence: 65%

Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation

et al. 1999

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The high risk human papillomavirus (HPV) type 16 E7 protein a ects cell growth control and promotes transformation by interfering with functions of cellular proteins. A key target of E7 is the tumor suppressor protein p105RB. Although this interaction is required for E7-dependent transformation, other cellular molecules must also be involved, because some E7 mutants that have reduced transforming abilities still bind to p105RB. In order to identify additional proteins that interact with E7 and that may be responsible to mediate its transforming function, we have used the C-terminal half of E7 in a yeast two-hybrid screen. We identi®ed the fork head domain transcription factor M phase phosphoprotein 2 (MPP2) as an interaction partner of E7. Speci®c interaction of the two proteins both in vitro and in vivo in mammalian cells was detected. The interaction of MPP2 with E7 is functionally relevant since MPP2 enhances the E7/Ha-Ras co-transformation of rat embryo ®broblasts. In addition HPV16 E7, but neither non-transforming mutants of HPV16 E7 nor low risk HPV6 E7, was able to stimulate MPP2-speci®c transcriptional activity. Thus, MPP2 is a potentially important target for E7-mediated transformation.

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Section: Discussionsupporting

confidence: 65%

Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation

et al. 1999

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“…In vitro studies have shown that for high-risk HPV: i) the binding of E7 to Rb abrogates the G1/S checkpoint (Thomas et al, 1998); ii) HPV E7 binds cyclin A and E (McIntyre et al, 1996) resulting in prolonged S phase or S phase arrest; and iii) E7 inhibits cyclin E-associated kinase and up-regulates cyclin A (Schulze et al, 1998). These observations are consistent with our findings in low-grade SIL.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Keratinocyte Immortalization in High-Grade Squamous Intraepithelial Lesions of the Cervix Infected with High-Risk Human Papillomaviruses

Southern

McDicken

Herrington

2000

Laboratory Investigation

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SUMMARY:In this study, we demonstrate that expression of cyclin B protein is up-regulated and persists into the upper epithelial layers in parallel with cyclin A expression in high-grade squamous intraepithelial lesions (SIL) infected with human papillomaviruses 16, 31, 33, 51, 58, 66, and 67 (n ϭ 33). In contrast, low-grade SIL infected with human papillomaviruses 16, 18, 31, 33, 39, 51, 52, 56, 58, and 66 (n ϭ 27) show weaker cyclin B expression confined to basal and parabasal cells despite extension of cyclin A and Ki67 expression into superficial cells. Moreover, aneusomy is present in 20% of the high-grade lesions but in none of the low-grade lesions. The persistent expression of cyclin B in high-grade SIL, and the restriction of aneusomy to high-grade SIL suggest that there is cell cycle progression. In combination with in vitro studies, this provides evidence that high-grade SIL lesions have undergone immortalization. (Lab Invest 2000, 80:539-544).C yclins, cyclin-dependent kinases (CDK), and CDK inhibitors control cell cycle progression and genomic integrity. They ensure the coordinated passage of cells through the cell cycle and provide surveillance mechanisms or checkpoints before the S and M phases to prevent abnormal DNA replication (Grana and Reddy, 1995). In vitro, high-risk human papillomaviruses (HPV) disrupt these cellular checkpoints, inducing mitotic defects and karyotypic abnormalities through the interactions of E6 and E7 proteins with the G1/S cell cycle regulators p53 and pRb, cyclins A and E, CDK 2, and CDK inhibitors p21 WAF1/CIP1 and p27 KIP1 (Galloway and McDougall, 1996; ZerfassThome et al, 1996). Moreover, up-regulation of cdc2-associated histone H1 activity by HPV 16 E6 in transfected primary human keratinocytes results in a decreased vigilance of mitotic checkpoints . In a recent in vivo study of low-grade cervical squamous intraepithelial lesions (SIL) (Southern and Herrington, 1998), we reported up-regulation of cyclin A, cyclin B and cyclin E expression by both low-risk and high-risk HPV infection. Cyclin D1 was overexpressed in 92% of lesions infected with low-risk HPV types but was absent in 87% of lesions infected with high-risk HPV types. The morphological pattern of cyclin expression was suggestive of S phase arrest/prolongation or upregulation of cyclin proteins to affect viral DNA replication. Tetrasomy occurred in lesions infected only with high-risk HPV, providing further evidence that G1/S and G2/M cell cycle checkpoints are abnormal in low-grade SIL infected with high-risk HPV.In vitro, cellular immortalization induced by transfection of high-risk HPV DNA into primary keratinocytes is accompanied by elevated levels of cyclin B, cyclin A and p34 cdc2 proteins (Steinmann et al, 1994). Immortalization is also associated with structural chromosome abnormalities (Solinas-Toldo et al, 1997) and activation of telomerase (Steenbergen et al, 1996). Moreover, analysis of naturally occurring lesions has recently demonstrated telomerase activation in almost all invasive cervica...

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“…Cip1 and causes a deregulated expression of cyclin E (McIntyre et al, 1996;Martin et al, 1998) thereby creating an aberrant S phase-like state that supports viral replication (Munger et al, 2001). How these activities can trigger centriole overduplication within a time period that corresponds to approximately a single cell-division cycle (Duensing et al, 2004(Duensing et al, , 2006a in currently unknown.…”

Section: Introductionmentioning

confidence: 99%

Centriole overduplication through the concurrent formation of multiple daughter centrioles at single maternal templates

et al. 2007

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Abnormal centrosome numbers are detected in virtually all cancers. The molecular mechanisms that underlie centrosome amplification, however, are poorly characterized. Based on the model that each maternal centriole serves as a template for the formation of one and only one daughter centriole per cell division cycle, the prevailing view is that centriole overduplication arises from successive rounds of centriole reproduction. Here, we provide evidence that a single maternal centriole can concurrently generate multiple daughter centrioles. This mechanism was initially identified in cells treated with the peptide vinyl sulfone proteasome inhibitor Z-L 3 VS. We subsequently found that the formation of more than one daughter at maternal centrioles requires cyclin E/cyclin-dependent kinase 2 as well as Polo-like kinase 4 and that overexpression of these proteins mimics this phenotype in the absence of a proteasome inhibitor. Moreover, we show that the human papillomavirus type 16 E7 oncoprotein stimulates aberrant daughter centriole numbers in part through the formation of more than one daughter centriole at single maternal templates. These results help to explain how oncogenic stimuli can rapidly induce abnormal centriole numbers within a single cell-division cycle and provide insights into the regulation of centriole duplication.

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Human Papillomavirus E7 Oncoproteins Bind a Single Form of Cyclin E in a Complex with cdk2 and p107

Cited by 134 publications

References 5 publications

Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation

Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation

Evidence for Keratinocyte Immortalization in High-Grade Squamous Intraepithelial Lesions of the Cervix Infected with High-Risk Human Papillomaviruses

Centriole overduplication through the concurrent formation of multiple daughter centrioles at single maternal templates

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