title: A cancer cell-specific inducer of apoptosis.
abstract: Human papillomavirus (HPV) DNA is found in virtually all cervical cancers, strongly suggesting that these viruses are necessary to initiate this disease. The HPV E2 protein is required for viral replication, but E2 expression is usually lost in HPV-transformed cells because of the integration of viral DNA into the host chromosome. Several studies have shown that the reintroduction of E2 into HPV-transformed cells can induce growth arrest and apoptotic cell death. This raises the possibility that E2 could be useful in the treatment of HPV-induced disease. However, the effects of E2 on cell proliferation are not limited to HPV-transformed cells. The E2 protein from HPV type 16 can induce apoptosis via at least two pathways. One pathway involves the binding of E2 to p53 and operates in HPV-transformed cells, many non-HPV-transformed cell lines, and untransformed normal cells. The second pathway requires the binding of E2 to the viral genome and operates only in HPV-transformed cells. A mutation in E2 that significantly reduces the binding of this protein to p53 abrogates the induction of apoptosis in non-HPV-transformed cells and normal cells, but has no effect on the ability of the mutated protein to induce apoptosis in HPV-transformed cells. Here we show that a chimeric protein consisting of this mutant of E2, fused to the herpes simplex virus type 1 VP22 protein, can traffic between cells in a three-dimensional tumor model and induce apoptosis in HPV-transformed cells with high specificity. This cancer cell-specific inducer of apoptosis may be useful in the treatment of cervical cancer and other HPV-induced diseases.
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Green
authors.forename: Craig
authors.initials: C
authors.lastname: Brown
authors.forename: Geraldine E
authors.initials: GE
authors.lastname: Roeder
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Southgate
authors.forename: Kevin
authors.initials: K
authors.lastname: Gaston
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics*; D005434:Flow Cytometry; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000473:pathology*; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000502:physiology*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome; D015678:Viral Structural Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D015678:Viral Structural Proteins; C073413:herpes simplex virus type 1 protein VP22; C076036:oncogene protein E2, Human papillomavirus type 1