Abstract
Human papillomavirus (HPV) E2 gene disruption is one of the key features of HPV-induced cervical malignant transformation. Though it is thought to prevent progression of carcinogenesis, the pro-apoptotic function of E2 protein remains poorly understood. This study shows that expression of HPV16 E2 induces apoptosis both in HPV-positive and -negative cervical cancer cell lines and leads to hyperactivation of caspase-8 and caspase-3. Activation of these signaling factors is responsible for the observed sensitivity to apoptosis upon treatment with anti-Fas antibody or TNF-α. In addition, immunoprecipitation experiments clearly show an interaction between HPV16 E2 and c-FLIP, a key regulator of apoptotic cell death mediated by death receptor signaling. Moreover, c-FLIP and a caspase-8 inhibitor protect cells from HPV16 E2-mediated apoptosis. Overexpression of c-FLIP rescues cervical cancer cells from apoptosis induced by HPV16 E2 protein expression. The data suggest that HPV16 E2 abrogates the apoptosis-inhibitory function of c-FLIP and renders the cell hypersensitive to the Fas/FasL apoptotic signal even below threshold concentration. This suggests a novel mechanism for deregulation of cervical epithelial cell growth upon HPV-induced transformation, which is of great significance in developing therapeutic strategies for intervention of cervical carcinogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal, Murine-Derived
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
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Caspase 3 / genetics
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Caspase 3 / metabolism*
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Caspase 8 / genetics
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Caspase 8 / metabolism*
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Cell Line, Tumor
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Female
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Gene Expression / drug effects
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Humans
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Oncogene Proteins, Viral / genetics
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Oncogene Proteins, Viral / metabolism*
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Papillomaviridae / genetics
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Papillomaviridae / metabolism
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Receptors, Death Domain / metabolism
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Signal Transduction* / drug effects
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / virology
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Murine-Derived
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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DNA-Binding Proteins
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FAIM protein, human
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Oncogene Proteins, Viral
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Receptors, Death Domain
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha
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anti-Fas monoclonal antibody
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oncogene protein E2, Human papillomavirus type 1
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Caspase 3
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Caspase 8