The Human Papillomavirus E6 protein and its contribution to malignant progression

Mantovani, Fiamma; Banks, Lawrence

doi:10.1038/sj.onc.1204869

Cited by 468 publications

(382 citation statements)

References 177 publications

(135 reference statements)

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“…20,21 This study further elucidates the mechanisms employed by E6 to modulate cellular responses to death stimuli. Cell death induced by TNF, Fas and TRAIL is transmitted through FADD and caspase 8 from cell surface receptors, to executioner caspases.…”

Section: Discussionmentioning

confidence: 82%

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Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

2006

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Viruses have developed sophisticated strategies to evade host defenses and facilitate the production and spread of progeny. In this study, we show that transfection of the human papillomavirus (HPV) 16 E6 oncogene into HCT116 cells provides protection from tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. Additionally, we demonstrate that the protection provided by E6 is dose-dependent because higher levels of E6 provide greater protection. The mechanism underlying this protection involves a rapid reduction in the protein levels of both Fasassociated death domain (FADD) and procaspase 8, which results in suppression of the activation of caspases 8, 3 and 2. Interestingly, E6 does not interfere with the mitochondrial apoptotic pathway even though HCT116 cells have been classified as type II cells with regard to TRAIL signaling. These findings demonstrate that E6 has a more generalized effect on signaling by death ligands than was previously thought and support the notion that E6 can utilize p53-independent mechanisms to modulate cell survival.

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Section: Discussionmentioning

confidence: 82%

“…The E6 oncoprotein of high-risk HPVs, such as HPV 16, plays a pivotal role in the pathophysiology of cervical cancer (reviewed in Mantovani and Banks 20 and Longworth and Laimins 21 ), which accounts for a large number of deaths among women worldwide. 22,23 One of the primary targets of E6 is the tumor suppressor p53.…”

Section: Introductionmentioning

confidence: 99%

Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

2006

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“…For example, one of their oncoproteins, E6, interacts with p53, a tumor suppressor, and induces its proteolytic degradation by recruiting E6-associated protein (E6AP), an E3 ubiquitin ligase (Scheffner et al, 1990;Huibregtse et al, 1993). In addition to p53-related functions, E6 redirects many other cellular pathways to the neoplastic state, favoring viral infection (Mantovani and Banks, 2001). Recently, E6 has been shown to interact with PDZ (PSD-95/Disc large/ZO-1) domain proteins such as hDLG (Kiyono et al, 1997;Lee et al, 1997), hScrib (Nakagawa and Huibregtse, 2000), MAGI-1,-2,-3 Thomas et al, 2001Thomas et al, , 2002 and MUPP1 .…”

Section: Introductionmentioning

confidence: 99%

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation

Jeong

Kim

et al. 2006

Oncogene

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The PDZ proteins such as hDLG, hScrib and MAGIs function as the membrane-associated protein scaffolds and have been shown to interact with the high-risk human papillomavirus (HPV) E6s. In this report, we identify a Golgi-associated PDZ protein, cystic fibrosis transmembrane regulator-associated ligand (CAL) as a cellular target of HPV16 E6 by the proteomic approach. The carboxy-terminal PDZ-binding motif of HPV16 E6 specifically interacts with the PDZ domain of CAL, and the interaction enhances proteasome-mediated degradation of CAL. HPV16 E6 interacts with CAL more strongly and degrades it better than HPV18 E6 owing to the more compatible PDZ-binding motif. CAL is ubiquitinated by the E6/E6-associated protein (E6AP) complex or by E6AP alone, albeit less efficiently, which indicates that it could be a normal target of E6AP. Although it downregulates CAL at the transcript level, small interfering RNA-induced depletion of HPV16 E6 in Caski cells stabilizes CAL at the protein level, suggesting that HPV16 E6 mediates the proteasomal degradation of CAL in HPV-positive cervical cancer cells. HPV16 E6 may tightly regulate the vesicular trafficking processes by interacting with CAL, and such a modification can contribute to the development of cervical cancer.

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“…11 Interactions of the high-risk HPV oncogene products E6 and E7 with two cardinal cellular regulators of the cell cycle, the tumor suppressor protein 53 (p53) and the retinoblastoma gene product (pRb), respectively, are of prime importance for HPV-associated HNSC carcinogenesis. 14,15 The E6 protein binds wild type (wt)-p53, triggering its ubiquitin-mediated degradation or directly inactivates wt-p53 by complex formation. The induced malfunction of wt-p53 causes the accumulation of DNA mutations, thus increasing the genetic instability of the cells, an instance likewise described for mutated p53.…”

mentioning

confidence: 99%

p16^INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer

Hoffmann¹,

Ihloff²,

Görögh³

et al. 2010

Intl Journal of Cancer

121

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The causal role of human papillomaviruses (HPV) in squamous cell carcinogenesis of tonsillar cancers (TSCC) depends on the activity of the viral oncoproteins E6 and E7, leading to inactivation of the cellular tumor suppressor p53 and the retinoblastoma gene product pRb. Because of the negative feedback mechanisms, the pRb inactivation causes an increase of the inhibitor of the cyclin-dependent kinases p16 INK4a . In 39 TSCC specimens, genotyping based on the amplification of HPV DNA was carried out using PCR by applying HPV type-specific oligonucleotides. Subsequently, amplicons were hybridised with fluorescence-labeled complementary probes using the Southern blot technology. For HPV E6/E7 mRNA expression, Northern hybridization and RT-PCR were performed, and for p16 INK4a detection, immunohistochemistry was performed. With 21/39 (53%) HPV-positives, the detection rate is within the range that can be expected in TSCC. The E6/E7 oncogene mRNA was detectable in 11 cases, 10 of which showed positive signals after p16 INK4a staining. Albeit the small study group was investigated, the correlation of the HPV DNA status with the p16 INK4a expression was of statistical significance (p 5 0.02). Kaplan-Meier estimations revealed better survival outcome for patients with HPV-positive tumors with detectable E6/E7 mRNA and p16 INK4a overexpression (p 5 0.02, median observation time 29 months). As mRNA expression tests are not routinely available in many clinical diagnostic laboratories, and based on the high correlation of p16 INK4a staining with HPV E6/E7 mRNA expression, in conclusion we suggest for a deeper exploration for the use of p16 INK4a as a surrogate marker with the potential to impact the standard of care of HPV DNA-positive head and neck carcinomas.Malignant tumors of the upper aerodigestive tract account for $7% of all cancers worldwide, 1 with squamous cell carcinomas (SCCs) constituting the largest portion among the different tumor entities. 2 Even though a majority of SCCs of the head and neck (HNSCC) seems associated to etiologic factors as carcinogenetic substances in tobacco smoke and alcohol, 3 an increase of especially younger patients without reported misuse of these environmental factors in history has been recognized. 4 Therefore, an increase in knowledge of other factors such as the infection with human papillomaviruses (HPV) promoting carcinogenesis in especially the latter patient group gains in importance.Epidemiologic data demonstrate HPV DNA prevalences of about 20-30% concerning all anatomical tumor sites of the head and neck region, 4-6 with the SCC of the Waldeyer's tonsillar (squamous cell carcinogenesis of tonsillar cancers, TSCC) ring showing an HPV DNA-positive rate of up to 60% as particularly predestined for an infection with HPV. 4,5,7 Recent data from Sweden describe HPV DNA infections in tonsillar carcinomas in even up to 85% of the investigated patients. 8 HPV DNA-positive HNSCCs, again with accentuation of those derived from the Waldeyer's tonsillar ring, are considered as being ...

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The Human Papillomavirus E6 protein and its contribution to malignant progression

Cited by 468 publications

References 177 publications

Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation

p16^INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer

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The Human Papillomavirus E6 protein and its contribution to malignant progression

Cited by 468 publications

References 177 publications

Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation

p16INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer

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p16^INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer