Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1

Abstract

The mitotic spindle checkpoint protein Bub1 has been found to be mutated at low frequency in certain human cancers characterized by aneuploidy. Simian virus 40 large T antigen efficiently immortalizes rodent cells and occasionally transforms them to tumorigenicity. T antigen can also cause genomic instability, inducing chromosomal aberrations and aneuploidy. Here, we report an interaction between Bub1 and T antigen. T antigen coimmunoprecipitates with endogenous Bub1 and Bub3, another component of the spindle checkpoint complex. Genetic analysis demonstrates that the interaction of T antigen with Bub1 is not required for immortalization but is closely correlated with transformation. T antigen induces an override of the spindle checkpoint dependent on Bub1 binding. This interaction with proteins of the spindle checkpoint machinery suggests another role for T antigen and provides insight into its ability to cause chromosomal aberrations, aneuploidy, and transformation.

HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint

“…SV40T antigen interaction with Bub1 promoted endoreduplication under nocodazole treatment (Cotsiki et al, 2004). Tax was reported to bind Mad1 (Jin et al, 1998) and recently to the CDC20-associated APC/C (Liu et al, 2005), prematurely activating the APC/C.…”

“…Some viral oncoproteins such as Tax and simian virus40 (SV40) T antigen interact with mitotic checkpoint components and these interactions contribute to aberrant mitotic phenotypes (Cotsiki et al, 2004;Liu et al, 2005). Similarly, HBx-induced multinucleated cells under microtubule-damaging conditions (Lee et al, 2002) could be potentially mediated through defects in the mitotic checkpoint.…”

Loss of LIN9, a member of the DREAM complex, cooperates with SV40 large T antigen to induce genomic instability and anchorage-independent growth

“…Early-passage (p2) Lin9 fl/f CreER T2 MEFs were infected with retroviral expression constructs encoding SV40 LT, LT K1 or LTD434-44 as described (Cotsiki et al, 2004;Gagrica et al, 2004). Cells were selected with 400 mg/ml neomycin for 5 days.…”

Cytogenetic characterization of HB2 epithelial cells from the human breast

“…It is widely acknowledged that the process of transformation and immortalization of cell lines via SV40 T antigen may cause genetic hypervariability and genomic instability with induction of chromosomal aberration and aneuploidy, probably due to the binding of the viral oncoprotein to components of the mitotic spindle checkpoint, such as Bub1, and consequent genomic destabilization (Ray et al 1990;Cotsiki et al 2004). Despite their ever-growing utilization as "normal" control in parallel with breast cancer cell lines in assays aimed to evaluate several different features of neoplastic cell behavior to our knowledge, no literature data have so far appeared concerning the chromosomal characterization of the HB2 cells in order to gain information on possible anomalies concerning the number and structure of the chromosomes.…”