title: The viral death effector Apoptin reveals tumor-specific processes.
abstract: Several natural proteins, including the cellular protein TRAIL and the viral proteins E4orf4 and Apoptin, have been found to exert a tumor-preferential apoptotic activity. These molecules are potential anti-cancer agents with direct clinical applications. Also very intriguing is their possible utility as sensors of the tumorigenic phenotype. Here, we focus on Apoptin, discussing recent research that has greatly increased our understanding of its tumor-specific processes. Apoptin, which kills tumor cells in a p53- and Bcl-2-independent, caspase-dependent manner, is biologically active as a highly stable, multimeric complex consisting of 30 to 40 monomers that form distinct superstructures upon binding cooperatively to DNA. In tumor cells, Apoptin is imported into the nucleus prior to the induction of apoptosis; this contrasts with the situation in primary or low-passage normal cell cultures where nuclear translocation of Apoptin is rare and inefficient. Apoptin contains two autonomous death-inducing domains, both of which exhibit a strong correlation between nuclear localization and killing activity. Nevertheless, forced nuclear localization of Apoptin in normal cells is insufficient to allow induction of apoptosis, indicating that another activation step particular to the tumor or transformed state is required. Indeed, a kinase activity present in cancer cells but negligible in normal cells was recently found to regulate the activity of Apoptin by phosphorylation. However, in normal cells, Apoptin can be activated by transient transforming signals conferred by ectopically expressed SV40 LT antigen, which rapidly induces Apoptin's phosphorylation, nuclear accumulation and the ability to induce apoptosis. The region on LT responsible for conferring this effect has been mapped to the N-terminal J domain. In normal cells that do not receive such signals, Apoptin becomes aggregated, epitope-shielded and is eventually degraded in the cytoplasm. Finally, Apoptin interacts with various partners of the human proteome including DEDAF, Nmi and Hippi, which may help to regulate either Apoptin's activation or execution processes. Taken together, these recent advances illustrate that elucidating the mechanism of Apoptin-induced apoptosis can lead to the discovery of novel tumor-specific pathways that may be exploitable as anti-cancer drug targets.
authors.affiliation: Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: J L
authors.initials: JL
authors.lastname: Rohn
authors.forename: M H M
authors.initials: MH
authors.lastname: Noteborn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D055592:Biophysical Phenomena; D001703:Biophysics; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D036022:Capsid Proteins; D020169:Caspases / Q000378:metabolism; D002467:Cell Nucleus / Q000821:virology; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D017727:Chicken anemia virus / Q000472:pathogenicity / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020543:Proteome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036022:Capsid Proteins; D004268:DNA-Binding Proteins; D020543:Proteome; C091717:VP3 protein, Chicken anemia virus; D020169:Caspases