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 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.
Vogt
M
M
Deutsches Krebsforschungszentrum, Arbeitsgruppe Molekulare Therapie Virus-assoziierter Tumore (F065), Im Neuenheimer Feld 242, Heidelberg, Germany.
Butz
K
K
Dymalla
S
S
Semzow
J
J
Hoppe-Seyler
F
F
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases