We have discovered an interesting set of functional interactions among three proteins: SV40 Large T antigen (LT), the p53 tumor suppressor protein and the mitotic kinase Bub1. Bub1 is a member of the family of checkpoint proteins that monitor the assembly of the mitotic spindle, and has been found to be mutated in certain human cancers characterized by aneuploidy. LT antigen can also cause genomic instability by inducing chromosomal aberrations and aneuploidy. Genetic analysis demonstrates that interaction of T antigen with Bub1 is not required for immortalization but is necessary for T antigen to drive viral replication and transform. Notably LT appears to act as a scaffold bringing Bub1 to p53, which then is phosphorylated on ser37 directly by Bub1 and on ser15, indirectly by a second kinase, leading to the stabilization of p53. Preliminary data suggests that this stabilization fo p53 is necessary for transformation by LT at least in certain circumstances. Also of note is finding that downregulating Bub1 function either by LT expression or by RNAi against Bub1 in the absence of LT, results in p53 dependent cellular senescence, accompanied by phosphorylation of ser37. Recently another group has demonstrated that ras induced senescence, which we can block with a dominant negative allele of Bub1, is also dependent on phosphorylation of p53 at serine 37. The key questions in the context of this grant are how Bub1 contributes to LT mediated replication and transformation and to suppressing tumor formation via senescence in the absence of LT. We can imagine several possible mechanisms: LT may use Bub1 to regulate replication and transformation via its direct phosphorylation of p53, via Bub1 mediated phosphorylation of other targets in the LT complex or more indirectly via by perverting Bubl's role in regulating genome stability. These mechanisms need not be mutually exclusive. Obviously similar mechanisms may be in play as Bub1 guards """"""""normal"""""""" cells from transformation by promoting senescence. In this application we propose to probe each of these mechanisms in turn.
We are studying the transformation mechanisms employed by the small DNA tumor virus denoted SV40. This virus causes oncogeneic transformation by modulating the actions of the same host cell proteins that are damaged by mutations in real human tumors. Thus we expect our studies on SV40 to aide in understanding and ultimately curing human tumors.
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