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Sara Maria Cigna, Antoine Forget, Laure Bihannic, Marc Remke, Sandrine Humbert, Michael D. Taylor, Anna Lasorella, Olivier Ayrault, MB-18
POST-TRANSLATIONAL REGULATION OF ATOH1: FROM CEREBELLAR DEVELOPMENT TO MEDULLOBLASTOMA FORMATION, Neuro-Oncology, Volume 17, Issue suppl_3, June 2015, Page iii23, https://doi.org/10.1093/neuonc/nov061.94Close - Share Icon Share
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Medulloblastoma (MB), a tumor of the cerebellum, is the most common malignant pediatric tumor of the central nervous system. Human MBs have been classified by gene expression profiling into four subgroups. A subgroup of human MBs (∼25%) harbors constitutive activation of the Sonic Hedgehog (SHH) signaling pathway. Atoh1, a proneural basic helix-loop-helix transcription factor is essential for cerebellum development and collaborates with SHH signaling for the formation of SHH MB in vivo. Because Atoh1 acts as a lineage dependency transcription factor in SHH MB, mechanisms controlling Atoh1 expression are keen interest in the field. However, how this master transcription factor is regulated has remained poorly understood. Using a proteomic approach we recently described a functional interaction between Atoh1 and the E3 ubiquitin ligase Huwe1 during cerebellar development. We uncovered that SHH regulates Atoh1 degradation in a phospho- and E3-dependent manner in cerebellar granule neuron progenitors. In human SHH MB, low HUWE1 expression is associated with poor prognosis. These results led us to deepen the relationship between Huwe1 and Atoh1 in SHH MB formation. More specifically, we wish to explore whether Huwe1 could cooperate with the constitutive activation of the SHH pathway for the formation of SHH MB in vivo.
