Neogenin1 is a Sonic Hedgehog target in medulloblastoma and is necessary for cell cycle progression
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2014Metadata
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Milla Brito, Luis Apolo
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Neogenin1 is a Sonic Hedgehog target in medulloblastoma and is necessary for cell cycle progression
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Abstract
The canonical Sonic Hedgehog (Shh)/Gli pathway plays multiples roles during central nervous system (CNS) development. To
elucidate the molecular repertoire of Shh mediators, we have recently described novel transcriptional targets in response to
Shh pathway modulation. Among them, we were able to identify Neogenin1 (Neo1), a death dependence receptor, as a new
direct Shh downstream regulator in neural precursor proliferation. As appropriate Shh signaling is required for cerebellar
growth and alterations cause Shh-driven medulloblastoma (MB), here we have addressed the role of the Shh/Neogenin1
interaction in the context of cerebellar development and cancer. We demonstrate that the Shh pathway regulates Neogenin1
expression in mouse models that recapitulate the Shh MB subtype. We show that the canonical Shh pathway directly
regulates the Neo1 gene acting through an upstream sequence in its promoter both in vitro and in vivo in granule neuron
precursor cells. We also identified and characterized a functional Gli-binding site in the first intron of the human NEO1 gene.
Gene expression profiling of more than 300 MB shows that NEO1 is indeed upregulated in SHH tumors compared to the other
MB subgroups. Finally, we provide evidence that NEO1 is necessary for cell cycle progression in a human MB cell line,
because a loss of function of NEO1 arrests cells in the G2/M phase. Taken together, these results highlight Neogenin1 as a
novel downstream effector of the Shh pathway in MB and a possible therapeutic target
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Artículo de publicación ISI
Patrocinador
They also
thank the Pew Foundation for their continuous support. This
work was supported by FONDAP 15090007 (V.P.), Fondecyt
grant 1110237 (V.P.), Fondecyt Postdoctoral 3100045 (L.A.M.)
and Dr. Mildred-Scheel foundation/German Cancer Aid (M.R.).
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Int. J. Cancer: 134, 21–31 (2014)
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