PP2A-dependent disruption of centrosome replication and cytoskeleton organization in Drosophila by SV40 small tumor antigen.
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.
Kotadia
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S
Department of Pharmacology, The Cecil and Ida Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9051, USA.
Kao
L R
LR
Comerford
S A
SA
Jones
R T
RT
Hammer
R E
RE
Megraw
T L
TL
D000818:Animals; D030801:Animals, Genetically Modified; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D018385:Centrosome / Q000276:immunology / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004330:Drosophila / Q000196:embryology / Q000378:metabolism* / Q000821:virology; D004625:Embryo, Nonmammalian; D019084:Fluorescent Antibody Technique, Indirect; D005982:Glutathione Transferase / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D009154:Mutation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D013539:Simian virus 40 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D054648:Protein Phosphatase 2