Papillomavirus E6 oncoproteins

Pol, Scott B. Vande; Klingelhutz, Aloysius J.

doi:10.1016/j.virol.2013.04.026

Cited by 304 publications

(281 citation statements)

References 302 publications

(376 reference statements)

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“…Since expression of low-risk HPV E7 proteins or an RB1 binding-competent/RB1 degradation-deficient HPV16 E7 mutant does not cause TP53 stabilization, E2F activation per se cannot be sufficient to cause TP53 activation (5). This is consistent with the finding that low-risk HPV E6 proteins did not evolve to target TP53 for degradation (7). Hence, despite its elegance and simplicity (Fig.…”

Section: Textbook Model Of Hpv Oncogenesissupporting

confidence: 81%

Human Papillomavirus Carcinogenesis: an Identity Crisis in the Retinoblastoma Tumor Suppressor Pathway

Münger

Jones

2015

J Virol

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bViruses are obligate intracellular parasites and need to reprogram host cells to establish long-term persistent infection and/or to produce viral progeny. Cellular changes initiated by the virus trigger cellular defense responses to cripple viral replication, and viruses have evolved countermeasures to neutralize them. Established models have suggested that human papillomaviruses target the retinoblastoma (RB1) and TP53 tumor suppressor networks to usurp cellular replication, which drives carcinogenesis. More recent studies, however, suggest that modulating the activity of the Polycomb family of transcriptional repressors and the resulting changes in epigenetic regulation are proximal steps in the rewiring of cellular signaling circuits. Consequently, RB1 inactivation evolved to tolerate the resulting cellular alterations. Therefore, epigenetic reprograming results in cellular "addictions" to pathways for survival. Inhibition of such a pathway could cause "synthetic lethality" in adapted cells while not markedly affecting normal cells and could prove to be an effective therapeutic approach. HUMAN PAPILLOMAVIRUS-ASSOCIATED CANCERS Papillomaviruses are ubiquitous viruses with 8-kb doublestranded circular genomes. They specifically infect squamous epithelial tissues and cause hyperplastic lesions, referred to as warts. Based on their tissue tropism, the ϳ200 human papillomavirus (HPV) types can be divided into mucosal and cutaneous types. Mucosal HPVs are classified as "low risk" and "high risk" for malignant progression of the lesions that they cause. Approximately 5% of all human cancers, including Ͼ99% of cervical carcinomas, many penile, vulvar, vaginal, and anal carcinomas, and a growing fraction of head and neck squamous cell carcinomas, are caused by high-risk HPVs (1). With an estimated 4,100 deaths in 2015 in the United States, one woman succumbs to cervical cancer approximately every 2 h in this country (and every 2 min worldwide) (2). Given the low vaccination rates in the United States and the fact that the available prophylactic vaccines do not inhibit malignant progression in individuals who are already infected, and because HPV-associated cancers often develop years to decades after the initial infection, these dire numbers are not likely to change in the foreseeable future. HPV-ASSOCIATED CANCERS ARE FUELED BY E6 AND E7 EXPRESSIONHigh-risk HPV-associated cancers are generally nonproductive infections, i.e., viral proteins are produced but no viral progeny is generated. Importantly, the HPV E6 and E7 genes are the only viral genes that are consistently expressed in these cancers. Although the recently identified, recurrent cellular mutations in cervical carcinoma likely also contribute to oncogenesis (3), cervical cancer lines remain "addicted" to E6/E7 expression, and extinguishing HPV E6/E7 expression in cervical cancer lines causes senescence (4).High-risk HPV E6 and E7 are potently oncogenic in cell-based transformation assays and in transgenic mouse models. In contrast, the low-risk HPV E6 and ...

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Section: Textbook Model Of Hpv Oncogenesissupporting

confidence: 81%

Human Papillomavirus Carcinogenesis: an Identity Crisis in the Retinoblastoma Tumor Suppressor Pathway

Münger

Jones

2015

J Virol

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“…Based on the resolved structure of HPV-16 E6 by Zanier et al [29], Cherry et al [30] revealed in their docking analysis study that few flavonoid compounds bind in the hydrophobic pocket of the E6 and E6AP interface and mimic the leucines in the conserved α-helical motif of E6AP. Another study also showed that the biological activities of E6 are mediated by the interaction of E6 with the LXXLL motif of E6AP [31]. In our study, the E6 protein of HPV-16 showed one LXXLL motif ( 103 LCDLL 107 ).…”

Section: Resultssupporting

confidence: 61%

Elucidating Molecular Interactions of Natural Inhibitors with HPV-16 E6 Oncoprotein through Docking Analysis

et al. 2014

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Human papillomavirus (HPV) infection is the leading cause of cancer mortality among women worldwide. The life-threatening infection caused by HPV demands the need for designing anticancerous drugs. In the recent years, different compounds from natural origins, such as carrageenan, curcumin, epigallocatechin gallate, indole-3-carbinol, jaceosidin, and withaferin, have been used as a hopeful source of anticancer therapy. These compounds have been shown to suppress HPV infection by different researchers. In the present study, we explored these natural inhibitors against E6 oncoprotein of high-risk HPV-16, which is known to inactivate the p53 tumor suppressor protein. A robust homology model of HPV-16 E6 was built to anticipate the interaction mechanism of E6 oncoprotein with natural inhibitory molecules using a structure-based drug designing approach. Docking analysis showed the interaction of these natural compounds with the p53-binding site of E6 protein residues 113-122 (CQKPLCPEEK) and helped the restoration of p53 functioning. Docking analysis, besides helping in silico validation of natural compounds, also helps understand molecular mechanisms of protein-ligand interactions.

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“…Also, although E2 is a regulator of SRSFs, we cannot rule out the possibility that other HPV proteins could be involved in controlling SRSF expression. For example, E6 and E7 may activate cellular transcription factors and control SRSF levels indirectly in differentiated keratinocytes (47,48).…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes

Klymenko

Hernandez-Lopez

MacDonald

et al. 2016

J Virol

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The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelial cell, suggesting a sophisticated interplay between host cell metabolism and virus replication. Previously, we demonstrated in differentiated keratinocytes in vitro and in vivo that HPV type 16 (HPV16) infection caused increased levels of the cellular SR splicing factors (SRSFs) SRSF1 (ASF/SF2), SRSF2 (SC35), and SRSF3 (SRp20). Moreover, the viral E2 transcription and replication factor that is expressed at high levels in differentiating keratinocytes could bind and control activity of the SRSF1 gene promoter. Here, we show that the E2 proteins of HPV16 and HPV31 control the expression of SRSFs 1, 2, and 3 in a differentiation-dependent manner. E2 has the greatest transactivation effect on expression of SRSF3. Small interfering RNA depletion experiments in two different models of the HPV16 life cycle (W12E and NIKS16) and one model of the HPV31 life cycle (CIN612-9E) revealed that only SRSF3 contributed significantly to regulation of late events in the virus life cycle. Increased levels of SRSF3 are required for L1 mRNA and capsid protein expression. Capsid protein expression was regulated specifically by SRSF3 and appeared independent of other SRSFs. Taken together, these data suggest a significant role of the HPV E2 protein in regulating late events in the HPV life cycle through transcriptional regulation of SRSF3 expression. IMPORTANCEHuman papillomavirus replication is accomplished in concert with differentiation of the infected epithelium. Virus capsid protein expression is confined to the upper epithelial layers so as to avoid immune detection. In this study, we demonstrate that the viral E2 transcription factor activates the promoter of the cellular SRSF3 RNA processing factor. SRSF3 is required for expression of the E4^L1 mRNA and so controls expression of the HPV L1 capsid protein. Thus, we reveal a new dimension of virus-host interaction crucial for production of infectious virus. SRSF proteins are known drug targets. Therefore, this study provides an excellent basis for developing strategies to regulate capsid protein production in the infected epithelium and the production of new virions.

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Papillomavirus E6 oncoproteins

Cited by 304 publications

References 302 publications

Human Papillomavirus Carcinogenesis: an Identity Crisis in the Retinoblastoma Tumor Suppressor Pathway

Human Papillomavirus Carcinogenesis: an Identity Crisis in the Retinoblastoma Tumor Suppressor Pathway

Elucidating Molecular Interactions of Natural Inhibitors with HPV-16 E6 Oncoprotein through Docking Analysis

Human Papillomavirus E2 Regulates SRSF3 (SRp20) To Promote Capsid Protein Expression in Infected Differentiated Keratinocytes

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