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

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...

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Bibliographic Details
Published in:	Oncogene Vol. 25; no. 29; pp. 4009 - 4015
Main Authors:	Vogt, M, Butz, K, Dymalla, S, Semzow, J, Hoppe-Seyler, F
Format:	Journal Article
Language:	English
Published:	England Nature Publishing Group 06-07-2006
Subjects:	Apoptosis Apoptosis - drug effects Apoptosis - genetics Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism bcl-2-Associated X Protein - antagonists & inhibitors bcl-2-Associated X Protein - genetics bcl-2-Associated X Protein - metabolism Caspase 3 Caspases - metabolism Cervical cancer Cervix Cytochrome c Cytochromes c - genetics Cytochromes c - metabolism Cytosol DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism E6 gene Enzyme Activation - genetics Female Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene Expression Regulation, Neoplastic - genetics Genetics HeLa Cells Human papillomavirus Humans Kinases Mitochondria Mitochondria - genetics Mitochondria - metabolism Oncogene Proteins, Viral - genetics Oncogene Proteins, Viral - metabolism Oncology Oncoproteins p53 Protein Papillomaviridae Phenotypes Protein Transport - genetics Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Repressor Proteins - genetics Repressor Proteins - metabolism Ribonucleic acid RNA RNA Interference - drug effects RNA, Small Interfering - genetics RNA, Small Interfering - pharmacology RNA-mediated interference Transcription Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - virology
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/sj.onc.1209429