Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis

Yuan, Huidong; Fu, Fenghua; Zhuo, Jiaying; Wang, Wei; Nishitani, Junko; An, Dong Sung; Chen, Irvin S. Y.; Li, Xuan

doi:10.1038/sj.onc.1208691

Cited by 71 publications

(60 citation statements)

References 52 publications

(49 reference statements)

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“…S3), 4 indicating that both E6 and Eg5 functions were inhibited. It may thus be possible to use other siRNAs specifically ablating cellular proteins up-regulated in cervical carcinoma cells (44) for codelivery with the 4C6 antibody in an attempt to induce detectable phenotypic changes of therapeutic value.…”

Section: Discussionmentioning

confidence: 99%

Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA

Courtête¹,

Sibler²,

Zeder‐Lutz³

et al. 2007

Molecular Cancer Therapeutics

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Cervical cancer is caused by high-risk types of human papillomaviruses (HPV) that encode the E6 and E7 oncogenes. Silencing of E6 gene expression in HPVpositive cell lines by transfection of small interfering RNA (siRNA) with cationic lipids restores the dormant p53 tumor suppressor pathway. Because cationic lipids can also be used for intracytoplasmic delivery of proteins, we tested whether the delivery of monoclonal antibodies that bind to HPV16 E6 and neutralize its biological activity in vitro could restore p53 function in tumor cells. Here, we show that the 4C6 antibody is efficiently delivered into the cell cytoplasm using a lipidic reagent used for siRNA transfection. The delivery of 4C6 resulted in the nuclear accumulation of p53 protein in CaSki and SiHa cells but not in HeLa cells. Furthermore, the antibody-mediated p53 response was dramatically increased when a peptide corresponding to the 4C6 epitope and bearing a COOHterminal cysteine residue was added to the transduction mixture. We found that a fraction of the added peptides were dimers that allowed the formation of antibody polymers adsorbed onto the lipidic matrix. With this system, the proliferation of CaSki and SiHa cells was strongly diminished, but no apoptosis was detectable. Remarkably, cell growth was almost totally suppressed by the addition of E6-specific siRNA to the transduction complex. The results indicate that the activity of E6 oncoprotein can be down-regulated in vivo by lipidmediated antibody delivery and that antibodies and siRNA act synergistically when codelivered. This novel targeting strategy is simple to implement and may find therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA

Courtête¹,

Sibler²,

Zeder‐Lutz³

et al. 2007

Molecular Cancer Therapeutics

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“…The E6 and E7 proteins from high-risk HPV are sufficient for the induction and maintenance of cellular transformation [6,31]. The over expression of E6 and E7 proteins within the proliferating cells alters several pathways, ultimately leading to tumour formation [33,38,44,49]. High-risk E6 protein binds and degrades p53 tumour suppressor protein [1,4,13,18,19,34,48].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analyses of genes differentially expressed by high-risk and low-risk human papilloma virus E6 oncoproteins

Ganguly

2015

VirusDis.

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Human papilloma virus is the causative agent for cervical cancer with 99 % of cervical cancer cases containing HPV. The high risk HPV-16, 18 and 31 are the major causative agents. The low risk HPV-6, 11 have been reported to cause penile, laryngeal, bronchogenic and oesophageal cancer. Since E6 oncoprotein is frequently over expressed in cancers, we did gene expression studies to compare between the E6 genes of high-risk (HPV18) or low-risk (HPV11)stably transfected in epithelial cell line EPC-2 or mock transfected with the basic vector pCDNA3.1. Microarray studies showed a total of 697 genes showing differential expression between the samples. Genes involved in several key cellular processes such as cell adhesion, angiogenesis, transcription regulation, cell cycle regulation and cell division showed altered expression between the samples. Gene Ontology mapping of 44 genes according cellular pathways revealed 13 pathways namely angiogenesis, alzhemier's, Wnt, p53, interleukin, TGF-b, cadherin, integrin, PI3-kinase, catennin, insulin, chemokine and G protein signalling pathways. The microarray results were confirmed by quantitative real-time PCR for some representative genes like IFI27, CTNNA1, OSMR, CYP1B1, TNFSF13, LAMA2 and COL5A3. Analysis of differentially expressed genes by high-risk and lowrisk HPV E6 proteins might help in identification of potential biomarkers for diagnosis, progression and therapy of oesophageal cancer. The understanding of mechanisms of activation of these genes as well as the function of gene products will give a further insight into their roles in oesophageal cancer.

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“…The viral E6 and E7 oncogenes are both regularly expressed in HPV-positive tumor cells and are necessary to maintain their transformed phenotype (zur Hausen, 2002). E6 exhibits antiapoptotic potential in various experimental settings (Pan and Griep, 1995;Sto¨ppler et al, 1998;Thomas and Banks, 1998;AguilarLemarroy et al, 2002;Filippova et al, 2004;Yuan et al, 2005), and the targeted inhibition of endogenous E6 activity induced apoptosis in HPV-positive cancer cells (Butz et al, 2000(Butz et al, , 2003Hengstermann et al, 2005;Kelley et al, 2005). Thus, the continuous presence of E6 is important for the viability of HPV-positive cancer cells, defining E6 as a promising target for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

“…CD95 or FADD), to the intrinsic, mitochondrial pathway (e.g. Bak or Bcl-2), or are regulators common to both pathways, such as the antiapoptotic c-IAP2 protein (Thomas and Banks, 1998;Aguilar-Lemarroy et al, 2002;Filippova et al, 2004;Yuan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

et al. 2006

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Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer in humans. The antiapoptotic viral E6 gene has been identified as a key factor for maintaining the viability of HPV-positive cancer cells. Although E6 has the potential to modulate many apoptosis regulators, the crucial apoptotic pathway blocked by endogenous E6 in cervical cancer cells remained unknown. Using RNA interference (RNAi), here, we show that targeted inhibition of E6 expression in cervical cancer cells leads to the transcriptional stimulation of the PUMA promoter, in a p53-dependent manner. This is linked to the activation and translocation of Bax to the mitochondrial membrane, cytochrome c release into the cytosol, and activation of caspase-3, in a PUMA-dependent manner. Moreover, inhibition of Bax expression by RNAi efficiently reverts the apoptotic phenotype, which results from inhibition of E6 expression. Thus, interference with the p53/PUMA/ Bax cascade is crucial for the antiapoptotic function of the viral E6 oncogene in HPV-positive cancer cells.

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Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis

Cited by 71 publications

References 52 publications

Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA

Suppression of cervical carcinoma cell growth by intracytoplasmic codelivery of anti-oncoprotein E6 antibody and small interfering RNA

Transcriptomic analyses of genes differentially expressed by high-risk and low-risk human papilloma virus E6 oncoproteins

Inhibition of Bax activity is crucial for the antiapoptotic function of the human papillomavirus E6 oncoprotein

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