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. 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.
Gualco
E
E
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, PA, USA.
Urbanska
K
K
Perez-Liz
G
G
Sweet
T
T
Peruzzi
F
F
Reiss
K
K
Del Valle
L
L
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007577:JC Virus / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D000077022:Survivin; D058570:TOR Serine-Threonine Kinases
D000952:Antigens, Polyomavirus Transforming; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017526:Receptor, IGF Type 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases