AffiliationDepartment of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom.
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AbstractHuman 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.
CitationA cancer cell-specific inducer of apoptosis. 2007, 18 (6):547-61 Hum. Gene Ther.
JournalHuman Gene Therapy
- Herpes simplex virus VP22-human papillomavirus E2 fusion proteins produced in mammalian or bacterial cells enter mammalian cells and induce apoptotic cell death.
- Authors: Roeder GE, Parish JL, Stern PL, Gaston K
- Issue date: 2004 Oct
- Diffusible VP22-E2 protein kills bystander cells and offers a route for cervical cancer gene therapy.
- Authors: Green KL, Southgate TD, Mulryan K, Fairbairn LJ, Stern PL, Gaston K
- Issue date: 2006 Feb
- HPV 16 E2 protein induces apoptosis in human and murine HPV 16 transformed epithelial cells and has antitumoral effects in vivo.
- Authors: Bermúdez-Morales VH, Peralta-Zaragoza O, Guzmán-Olea E, García-Carrancá A, Bahena-Román M, Alcocer-González JM, Madrid-Marina V
- Issue date: 2009
- The human papillomavirus (HPV) 16 E2 protein induces apoptosis in the absence of other HPV proteins and via a p53-dependent pathway.
- Authors: Webster K, Parish J, Pandya M, Stern PL, Clarke AR, Gaston K
- Issue date: 2000 Jan 7
- E2 proteins from high- and low-risk human papillomavirus types differ in their ability to bind p53 and induce apoptotic cell death.
- Authors: Parish JL, Kowalczyk A, Chen HT, Roeder GE, Sessions R, Buckle M, Gaston K
- Issue date: 2006 May