Journal Article

IGF-IR-dependent expression of Survivin is required for T-antigen-mediated protection from apoptosis and proliferation of neural progenitors

Del Valle, L, Urbanska, K, Sweet, T, Peruzzi, F, Perez-Liz, G, Reiss, K, Gualco, E

2010

Overview

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. Because 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 nontransgenic 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 antiapoptotic 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 antiapoptotic Survivin may be a critical step in JCV T-antigen-induced transformation, which in neural progenitors requires IGF-IR.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Antigens / Antigens, Polyomavirus Transforming - genetics / Antigens, Polyomavirus Transforming - physiology / Apoptosis / Apoptosis - physiology / Biochemistry / Biomedical and Life Sciences / Brain cancer / Cell Biology / Cell Cycle Analysis / Cell death / Cell Proliferation / Cells, Cultured / Child / DNA repair / Embryo, Mammalian - anatomy & histology / Embryo, Mammalian - physiology / Embryos / Genomes / Humans / Inhibitor of Apoptosis Proteins / Insulin / Insulin-like growth factors / Intracellular Signaling Peptides and Proteins - genetics / Intracellular Signaling Peptides and Proteins - metabolism / JC virus / JC Virus - physiology / Kinases / Life Sciences / Mice / Mice, Knockout / Microtubule-Associated Proteins - genetics / Microtubule-Associated Proteins - metabolism / Neurons - cytology / Neurons - physiology / Neurosciences / original-paper / Polyomavirus / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteins / Receptor, IGF Type 1 - genetics / Receptor, IGF Type 1 - metabolism / Repressor Proteins / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Signal transduction / Stem Cells / Stem Cells - cytology / Stem Cells - physiology / Survivin / TOR Serine-Threonine Kinases / Tumors