PP2A-dependent disruption of centrosome replication and cytoskeleton organization in Drosophila by SV40 small tumor antigen

• Published in: Oncogene Vol. 27; no. 49; pp. 6334 - 6346
• Main Authors: KOTADIA, S, KAO, L. R, COMERFORD, S. A, JONES, R. T, HAMMER, R. E, MEGRAW, T. L
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 23.10.2008
• Subjects: Actin; Animals; Animals, Genetically Modified; Antigen (tumor-associated); Antigen T (large); Antigens; Antigens, Polyomavirus Transforming - genetics; Antigens, Polyomavirus Transforming - immunology; Antigens, Polyomavirus Transforming - metabolism; Apoptosis; Biological and medical sciences; Cell Line; Cell physiology; Cell proliferation; Cell structures and functions; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Centrosome - immunology; Centrosome - metabolism; Centrosomes; Chromosome aberrations; Chromosome replication; Chromosomes; Cyclin E; Cytoskeleton; Cytoskeleton - genetics; Cytoskeleton - immunology; Cytoskeleton - metabolism; Cytoskeleton, cytoplasm. Intracellular movements; Deoxyribonucleic acid; DNA; DNA tumor viruses; DNA viruses; Drosophila; Drosophila - embryology; Drosophila - metabolism; Drosophila - virology; Embryo, Nonmammalian; Embryos; Fluorescent Antibody Technique, Indirect; Fundamental and applied biological sciences. Psychology; Genetic aspects; Genetics; Glutathione Transferase - chemistry; Glutathione Transferase - immunology; Glutathione Transferase - metabolism; Health aspects; Heterozygote; Immunohistochemistry; Insects; Lethality; Medical genetics; Medical sciences; Molecular and cellular biology; Mutation; Oncology; p53 Protein; Phenotypes; Phosphatases; Phosphoprotein phosphatase; Physiological aspects; Protein phosphatase; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - isolation & purification; Recombinant Fusion Proteins - metabolism; Simian virus 40; Simian virus 40 - genetics; Simian virus 40 - immunology; Simian virus 40 - metabolism; Supernumerary; Threonine; Tumor antigens; Tumor suppressor genes; Tumors; Viruses; United States; Chromosomal aberration; Insecta; Polyomavirus; Aneuploidy; PP2A; Papovaviridae; Simian virus 40; Carcinogenesis; Drosophilidae; Virus; Antigen; Arthropoda; Cytoskeleton; Replication; Tumor; Cyclin E; SV40 ST; Invertebrata; Drosophila melanogaster; Diptera; Centriole; Centrosome
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.254

Viruses of the DNA tumor virus family share the ability to transform vertebrate cells through the action of virus-encoded tumor antigens that interfere with normal cell physiology. They accomplish this very efficiently by inhibiting endogenous tumor suppressor proteins that control cell proliferation and apoptosis. Simian virus 40 (SV40) encodes two oncoproteins, large tumor antigen, which directly inhibits the tumor suppressors p53 and Rb, and small tumor antigen (ST), which interferes with serine/threonine protein phosphatase 2A (PP2A). We have constructed a Drosophila model for SV40 ST expression and show that ST induces supernumerary centrosomes, an activity we also demonstrate in human cells. In early Drosophila embryos, ST also caused increased microtubule stability, chromosome segregation errors, defective assembly of actin into cleavage furrows, cleavage failure, a rise in cyclin E levels and embryonic lethality. Using ST mutants and genetic interaction experiments between ST and PP2A subunit mutations, we show that all of these phenotypes are dependent on ST's interaction with PP2A. These analyses demonstrate the validity and utility of Drosophila as a model for viral oncoprotein function in vivo.