Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells

Hengstermann, Arnd; Linares, Laëtitia K.; Ciechanover, Aaron; Whitaker, Noel J.; Scheffner, Martin

doi:10.1073/pnas.98.3.1218

Cited by 176 publications

(104 citation statements)

References 38 publications

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“…The HPV E6-E7 are early genes associated with cell transformation (3). The expressed oncoprotein of HPV E6 degrades p53 protein through the cellular ubiquitin-protein ligase E6-AP pathway (22,23). The E7 oncoprotein binds to the retinoblastoma gene products, pRb, p107, cyclin A, AP-1 transcription factor, and the TATA box binding protein, TBP (24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Human papilloma virus DNA exposure and embryo survival is stage-specific

Henneberg

Patton

Jacobson

et al. 2006

J Assist Reprod Genet

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Purpose: Human papillomavirus (HPV) has been shown to disrupt late-stage implanting embryos. The objectives were (a) to assess the development of early embryos exposed to HPV DNA and (b) to analyze the blastocyst hatching process after HPV exposure. Methods:The study involved exposing two-cell and 4-8-cell mouse embryos to DNA fragments from either HPV type 16, type 18 or DQA1 (control). The embryos were incubated for 120 h and assessed. Results: HPV 16 and 18 inhibited two-cell embryo development. In contrast, delaying the exposure of HPV DNA until the 4-8-cell stage resulted in further embryonic development. There was 25.9% less blastocyst formed with HPV 16 exposure. Additionally, there were 25.9-31.8% more degenerated embryos with HPV 16 exposure. Conclusions:The study demonstrated embryo stage-specific effects of HPV on early development. The results suggested HPV exposure was linked to two-cell embryo demise and delaying the exposure of HPV until later embryo stages permitted embryo development. HPV 16 was shown to decrease blastocyst formation while HPV 18 inhibited the blastocyst hatching process.

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Section: Discussionmentioning

confidence: 99%

Human papilloma virus DNA exposure and embryo survival is stage-specific

Henneberg

Patton

Jacobson

et al. 2006

J Assist Reprod Genet

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“…the expression of viral oncogenes, this degradative pathway is inhibited and p53 is both stabilized and activated (Ashcroft and Vousden, 1999, for review). Recent experiments have indeed shown that in HPV-positive cancer cells the Mdm2 pathway is completely inactive, while p53 degradation depends entirely on E6 (Hengstermann et al, 2001). This indicates that E6 can target p53 for degradation under conditions when this would be normally inhibited, e.g.…”

Section: Interactions Between Hpv E6 and P53mentioning

confidence: 98%

The Human Papillomavirus E6 protein and its contribution to malignant progression

2001

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The Human Papillomavirus (HPV) E6 protein is one of three oncoproteins encoded by the virus. It has long been recognized as a potent oncogene and is intimately associated with the events that result in the malignant conversion of virally infected cells. In order to understand the mechanisms by which E6 contributes to the development of human malignancy many laboratories have focused their attention on identifying the cellular proteins with which E6 interacts. In this review we discuss these interactions in the light of their respective contributions to the malignant progression of HPV transformed cells. Oncogene (2001) 20, 7874 ± 7887.

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“…41). Thus, although it is formally possible that E6 is partially responsible for the shift of MCF-7 cells from senescence to apoptosis after adriamycin treatment, it is more probable that the elimination of p53 function is the mechanism for the conversion.…”

Section: Discussionmentioning

confidence: 99%

Adriamycin-induced Senescence in Breast Tumor Cells Involves Functional p53 and Telomere Dysfunction

Elmore¹,

Rehder

Di³

et al. 2002

Journal of Biological Chemistry

230

227

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Direct experimental evidence implicates telomere erosion as a primary cause of cellular senescence. Using a well characterized model system for breast cancer, we define here the molecular and cellular consequences of adriamycin treatment in breast tumor cells. Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in ␤-galactosidase, a marker of senescence. Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis, demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents. Stable introduction of hTERT, the catalytic protein component of telomerase, into MCF-7 cells caused an increase in telomerase activity and telomere length. Treatment of MCF-7-hTERT cells with adriamycin produced an identical senescence response as controls without signs of telomere shortening, indicating that the senescence after treatment is telomere length-independent. However, we found that exposure to adriamycin resulted in an overrepresentation of cytogenetic changes involving telomeres, showing an altered telomere state induced by adriamycin is probably a causal factor leading to the senescence phenotype. To our knowledge, these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening.Most normal somatic cells continually shorten their telomeres after each cell division because of incomplete replication at the end of linear chromosomes (1, 2). The original hypothesis stated that when telomeres have become sufficiently shortened, replicative senescence is induced (3, 4). Tumor suppressor proteins such as p53 are required for this senescence arrest. Most cells with indefinite proliferative ability (e.g. human tumors and their derivative cell lines) express the enzyme telomerase to maintain telomeres, which allows for the continued cellular proliferation characteristic of human cancer (5, 6). Telomerase is a cellular reverse transcriptase containing two strictly required elements: a protein component, hTERT, and an RNA element, hTR (7-9). hTERT serves as the catalytic subunit, whereas hTR is utilized by hTERT as the template for catalyzing the addition of telomeric DNA to the end of the chromosome. The introduction of telomerase into normal human cells provides for telomere maintenance, prevention of senescence, and an extension of life span, indicating that gradual telomere shortening is one of the factors contributing to the onset of cellular senescence (10, 11). Recent evidence suggests that although telomere length is an important trigger for the onset of senescence, increased telomere dysfunction results in a loss of chromosome end protection and induction of the senescence state (12). These novel findings show that senescence can be induced without net telomere shortening, and that while len...

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Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells

Cited by 176 publications

References 38 publications

Human papilloma virus DNA exposure and embryo survival is stage-specific

Human papilloma virus DNA exposure and embryo survival is stage-specific

The Human Papillomavirus E6 protein and its contribution to malignant progression

Adriamycin-induced Senescence in Breast Tumor Cells Involves Functional p53 and Telomere Dysfunction

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