Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein

Funk, Jens Oliver; Waga, Shiro; Harry, Jo Beth; Espling, Erik; Stillman, Bruce; Galloway, Denise A.

doi:10.1101/gad.11.16.2090

Cited by 475 publications

(397 citation statements)

References 59 publications

(71 reference statements)

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“…The HR-HPV E7 oncoproteins bind and degrade the retinoblastoma tumor suppressor protein (pRB) thereby releasing the transcription factor E2F which in turn induces the S-phase genes cyclin A and cyclin E (Munger et al, 2001). In concert, E7 also inactivates the cyclin inhibitors p21 Cip1 and p27 Kip1 (Zerfass-Thome et al, 1996;Funk et al, 1997). However, free E2F also activates p14 ARF which stabilizes p53 (Itoshima et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

et al. 2007

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Virus integration into the host genome is a characteristic step during cervical carcinogenesis. Experimental data provide evidence that integration could result in increased levels of oncogene (E6/E7) transcripts. This is the first study in which the level of viral transcripts is correlated to the physical state of the viral genome in cervical intraepithelial neoplasia (CIN) and cervical carcinomas (CxCa). Using the APOT-assay integrate-derived transcripts only were detected in 3/28 (11%) CIN and in 28/55 (51%) carcinomas, respectively. The remaining biopsies contained either episome-derived transcripts only or both mRNA species. SybrGreen real time reverse transcriptase-PCR assays were used to quantify viral gene expression for (i) all transcripts initiated from p97, (ii) full-length E6, (iii) E6*I and (iv) E5 transcripts. E6/E7 transcript levels showed a broad distribution but similar median values irrespective of histopathological grading and physical state of the viral genome. Biopsies with integrate-derived transcripts only generally lacked E5-specific mRNA. Our data do not support the hypothesis that HPV integration invariably results in high levels of oncogene transcripts. Instead, constitutive expression of oncogene transcripts rather than the level of expression appears to be decisive for transformation and the maintenance of the malignant phenotype.

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Section: Introductionmentioning

confidence: 99%

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

et al. 2007

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“…Even though the precise function of MPP2 is unclear, the potential role of MPP2 in S and M phase transitions may indicate why this protein is targeted by HPV16 E7. By stimulating the activity of MPP2 as transcriptional activator (Figure 7) HPV16 E7 might acquire the ability to modulate a set of cellular genes distinct from those regulated downstream of p105Rb and p21 (MuÈ nger and Phelps, 1993;Funk et al, 1997;Jones et al, 1997). The ability of HPV16 to enhance MPP2 function might be used to drive host cells into S phase and allow viral replication.…”

Section: Discussionmentioning

confidence: 99%

“…Recent ®ndings indicate that E7 can interact with p27 KIP1 and abrogate p27-dependent inhibition of cyclin E/CDK2 kinase and of cyclin A promoter activity (ZerfassThome et al, 1996). In addition E7 binds to p21 Cip1 and interferes with its ability to inhibit cyclin E/CDK2 and cyclin A/CDK2 kinase activities and proliferating cell nuclear antigen-dependent DNA replication (Funk et al, 1997;Jones et al, 1997). Also E7 interacts directly with proteins involved in regulating gene transcription, including the TATA-box binding protein (TBP) (Massimi et al, 1996), TBP-associated factor 110 of Drosophila melanogaster (TAF II 110) (Mazzarelli et al, 1995), and c-Jun (Antinore et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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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“…Probably E7 acts by repressing p27 inhibition on the cyclin A transactivation (Zerfass-Thome et al, 1997). The association of p21 with E7 has also been demonstrated and leads to the same restoring of the cdk2 function cdk2 (Jones et al, 1997;Funk et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours

et al. 1998

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Cell cycle proteins regulate the transitions from G1 to S and G2 to M phases. In higher eukaryotes, their function is controlled by intracellular cascades regulated by extracellular growth factors. We have studied in previously described transgenic mouse models for thyroid proliferative diseases the expression of the key proteins regulating the cell cycle by Western blotting and immunohistochemistry, and have correlated the observations with the known actions of the transgenes on the signal transduction cascades. In the adenosine A 2a receptor model, the cyclic AMP pathway, upstream of the Rb family cell division block, is constitutively activated. In the model expressing HPV 16 E7 protein, the Rb-like proteins are inhibited. Cyclin-dependent kinases cdk4, cdk2 and cdc2, and the associated cyclins D, E and A have been studied. Cyclin D3 appears as the major cyclin D subtype expressed in mouse thyroid epithelial cells in normal and transgenic mice. In the adenosine A 2a R model, all cell cycle proteins tested were accumulated. In the E7 model, all cell cycle proteins except for D-type cyclins and cdk4 were also accumulated. A similar pattern was observed in thyroids coexpressing both transgenes, suggesting a dominant e ect of E7 over the consequences of the cAMP cascade activation. The cyclin-dependent kinase inhibitors p21 cip1/waf1 and p27 kip1 were not downregulated in these proliferating thyroids which suggest other roles than the inhibition of the cell cycle progression.

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Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein

Cited by 475 publications

References 59 publications

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts

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

Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumours

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