Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes.
Signaling by the sonic hedgehog (Shh) pathway is essential for neural precursor population expansion during normal central nervous system (CNS) development, and is implicated in the childhood brain tumor, medulloblastoma. The proto-oncogene N-myc plays essential roles as a downstream effector of Shh proliferative effects in neural precursors of the cerebellum, where medulloblastomas arise. It is likely that N-Myc has analogous functions in medulloblastomas and other CNS tumors where it is highly expressed due to altered regulation or gene amplification. Myc destabilization occurs in response to phosphorylation by GSK-3beta. N-Myc degradation is required for cerebellar neural precursors to exit the cell cycle. During mitosis in cerebellar neural precursors, levels of N-Myc primed for phosphorylation by GSK-3beta increase, due to cdk1 complex activity towards N-Myc. GSK-3beta is kept in check by insulin-like growth factor signaling, which also plays critical roles in brain development and cancer. These findings indicate that therapeutic strategies targeting N-myc and the IGF pathway might be effective against medulloblastoma.
Knoepfler
Paul S
PS
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Kenney
Anna Marie
AM
D000818:Animals; D002454:Cell Differentiation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D053823:Hedgehog Proteins; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*
D053823:Hedgehog Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human; D015534:Trans-Activators; D038362:Glycogen Synthase Kinase 3