The Human Papillomavirus Type 16 E6 Oncoprotein Can Down-Regulate p53 Activity by Targeting the Transcriptional Coactivator CBP/p300

Zimmermann, Holger; Degenkolbe, Roland; Bernard, Hans‐Ulrich; O’Connor, Mark J.

doi:10.1128/jvi.73.8.6209-6219.1999

Cited by 293 publications

(133 citation statements)

References 80 publications

(114 reference statements)

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“…The Group 3 E6 mutants, for example, L50G, lost the ability to interact with E6AP ( Fig. 2B), as previously reported [Zimmermann et al, 1999]. These data indicate a close relationship between the ubiquitin-mediated degradation of the three tumor suppressor proteins by E6 and its interaction with E6AP.…”

Section: Ability Of E6 Mutants To Degrade the E6-dependent Substrate supporting

confidence: 87%

Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E6

et al. 2006

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Human scribble (hScrib), which was identified as substrate of human papillomavirus (HPV) E6 for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP, is a human homolog of Drosophila neoplastic tumor suppressor scribble, in which mutation causes loss of polarity and overgrowth of epithelia. Drosophila discs large (Dlg) is one of neoplastic tumor suppressors, which genetically links to scribble. E6 also targets human Dlg (hDlg) for ubiquitin-mediated degradation. Ubiquitin-protein ligase involved in this process has not been identified thus far. Here we investigated mechanism underlying degradation of three target proteins of E6, hScrib, hDlg, and p53 by using eighteen HPV 16 E6 mutants with single amino acid substitution. In vitro degradation ability of each E6 mutant was equivalent for these tumor suppressors. We investigated whether E6AP is involved in ubiquitin-mediated degradation of hDlg. In vitro binding assay revealed that hDlg formed ternary complex with E6-E6AP complex. The ability of E6 mutants to degrade these tumor suppressors was correlated with their ability to interact with E6AP. Furthermore, hDlg was targeted for in vitro ubiquitination in the presence of both E6 and E6AP. These data revealed that E6AP is extensively involved in the ubiquitin-mediated degradation of E6-dependent substrates as a cellular E3 ubiquitin-protein ligase.

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Section: Ability Of E6 Mutants To Degrade the E6-dependent Substrate supporting

confidence: 87%

Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E6

et al. 2006

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“…Different from those using fetal esophageal tissues or SV40 large T-antigen transfection, our immortalized cell line was derived from adult esophageal specimens and transfected with HPV-16, a definite carcinogen for esophageal cancer in northern China, 1 which should resemble natural esophageal carcinogenesis. E6 and/or E7 transfection have the ability to overcome cellular senescence by disruption of p53 or RB pathway, [17][18][19][20] but only those cells that are able to overcome crisis can be immortalized. Telomerase is believed to play the key role while cells escape the later limitation.…”

Section: Discussionmentioning

confidence: 99%

Early upregulation of cyclooxygenase‐2 in human papillomavirus type 16 and telomerase‐induced immortalization of human esophageal epithelial cells

Zhuang

Tsao

Deng

et al. 2008

J of Gastro and Hepatol

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“…1.5×10 5 cells were plated onto 6 well plates. The next day cells were transfected with 25nm siRNA targeting E2 (GCAGUUUGAUGGAGACAUAUU-Dharmacon) (15) or control siRNA targeting luciferase (Ambion) using Lipofectamine 2000 (Invitrogen). 16 hours later, transfected cells were washed with PBS and media replaced.…”

Section: Methodsmentioning

confidence: 99%

Human papillomavirus 16 E2 regulates keratinocyte gene expression relevant to cancer and the viral life cycle

Evans

James

Bristol

et al. 2018

Preprint

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14Human papillomaviruses (HPV) are causative agents in ano-genital and oropharyngeal cancers. 15 The virus must reprogram host gene expression to promote infection, and E6 and E7 contribute 16 to this via targeting of cellular transcription factors including p53 and pRb, respectively. The 17 HPV16 E2 protein regulates host gene expression in U2OS cells and in this study we extend 18 these observations into TERT immortalized oral keratinocytes (NOKs) that are capable of 19 supporting late stages of the HPV16 life cycle. We observed repression of innate immune genes 20 by E2 that are also repressed by the intact HPV16 genome in NOKs. RNA-seq data identified 21 167 up and 395 downregulated genes by E2; there was a highly significant overlap of the E2 22 regulated genes with those regulated by the intact HPV16 genome in the same cell type. siRNA 23 targeting of E2 reversed repression of E2 targeted genes. The ability of E2 to repress innate 24 immune genes was confirmed in an ano-genital immortalized keratinocyte cell line, N/Tert-1. 25 We present analysis of data from The Cancer Genome Atlas (TCGA) for HPV16 positive and 26 negative head and neck cancers (HNC) suggesting that E2 plays a role in regulation of the host 27 genome in cancers. Patients with HPV16 positive HNC with a loss of E2 expression exhibit a 28 worse clinical outcome and we discuss how this could, at least partially, be related to the loss of 29 E2 host gene regulation. 30 31 Importance 32 HPV16 positive tumors that retain expression of E2 have a better clinical outcome than those 33 that have lost E2 expression. It has been suggested that this is due to a loss of E2 repression of 34 E6 and E7 expression but this is not supported by data from tumors where there is not more E6 35 3 and E7 expression in the absence of E2. Here we report that E2 regulates host gene expression 36 and place this regulation in context of the HPV16 life cycle and HPV16 positive head and neck 37 cancers (the majority of which retain E2 expression). We propose that this E2 function may play 38 an important part in the increased response of HPV16 positive cancers to radiation therapy. 39 Therefore, host gene regulation by E2 may be important for promotion of the HPV16 life cycle, 40 and also for the response of HPV16 positive tumors to radiation therapy. 41 42 43 44 High risk human papillomaviruses (HR-HPV) are etiological agents in ano-genital and 45 oropharyngeal cancers (1). HPV16 is causative in around 50% of HPV positive cervical cancers 46 (HPV+CC) and 90% of HPV positive oropharyngeal cancers (HPV+OPC), the latter of which 47 has reached epidemic proportions over the past generation (2-5). 48 Following infection, HPV DNA ultimately reaches the nucleus where cellular factors induce 49 transcription from the viral genome. The viral oncogenes E6 and E7 create an environment that 50 promotes cellular proliferation and one aspect of this manipulation is the alteration of host gene 51 transcription. E7 binds to pocket proteins pRb, p130 and p107 and blo...

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The Human Papillomavirus Type 16 E6 Oncoprotein Can Down-Regulate p53 Activity by Targeting the Transcriptional Coactivator CBP/p300

Cited by 293 publications

References 80 publications

Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E6

Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E6

Early upregulation of cyclooxygenase‐2 in human papillomavirus type 16 and telomerase‐induced immortalization of human esophageal epithelial cells

Human papillomavirus 16 E2 regulates keratinocyte gene expression relevant to cancer and the viral life cycle

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