IGF-IR dependent expression of Survivin is required for T-Antigen mediated Protection from Apoptosis and Proliferation of Neural Progenitors

The Insulin-like Growth Factor-1 Receptor (IGF-IR) and the human polyomavirus JCV protein, T-Antigen cooperate in the transformation of neuronal precursors in the cerebellum, which may be a contributing factor in the development of brain tumors. Since it is not clear why T-Antigen requires IGF-IR for transformation, we investigated this process in neural progenitors from IGF-IR knockout embryos (ko-IGF-IR) and from their wild type non-transgenic littermates (wt-IGF-IR). In contrast to wt-IGF-IR, the brain and dorsal root ganglia of ko-IGF-IR embryos showed low levels of the anti-apoptotic protein Survivin, accompanied by elevated numbers of apoptotic neurons and an earlier differentiation phenotype. In wt-IGF-IR neural progenitors in vitro, induction of T-Antigen expression tripled the expression of Survivin, and accelerated cell proliferation. In ko-IGF-IR progenitors induction of T-Antigen failed to increase Survivin, resulting in massive apoptosis. Importantly, ectopic expression of Survivin protected ko-IGF-IR progenitor cells from apoptosis and siRNA inhibition of Survivin activated apoptosis in wt-IGF-IR progenitors expressing T-Antigen. Our results indicate that reactivation of the anti-apoptotic Survivin may be a critical step in JCV T-Antigen induced transformation, which in neural progenitors requires IGF-IR.