Cargando…

Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth

Treatment for medulloblastoma, the most common malignant brain tumor in children, remains limited to surgical resection, radiation, and traditional chemotherapy; with long-term survival as low as 50–60% for Sonic Hedgehog (Shh)-type medulloblastoma. We have shown that the transcription factor Atonal...

Descripción completa

Detalles Bibliográficos
Autores principales: Klisch, Tiemo J, Vainshtein, Anna, Patel, Akash J, Zoghbi, Huda Y
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736349/
https://www.ncbi.nlm.nih.gov/pubmed/29168692
http://dx.doi.org/10.7554/eLife.31181
_version_ 1783287357547479040
author Klisch, Tiemo J
Vainshtein, Anna
Patel, Akash J
Zoghbi, Huda Y
author_facet Klisch, Tiemo J
Vainshtein, Anna
Patel, Akash J
Zoghbi, Huda Y
author_sort Klisch, Tiemo J
collection PubMed
description Treatment for medulloblastoma, the most common malignant brain tumor in children, remains limited to surgical resection, radiation, and traditional chemotherapy; with long-term survival as low as 50–60% for Sonic Hedgehog (Shh)-type medulloblastoma. We have shown that the transcription factor Atonal homologue 1 (Atoh1) is required for Shh-type medulloblastoma development in mice. To determine whether reducing either Atoh1 levels or activity in tumors after their development is beneficial, we studied Atoh1 dosage and modifications in Shh-type medulloblastoma. Heterozygosity of Atoh1 reduced tumor occurrence and prolonged survival. We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling. Importantly, inhibition of Jak2 impairs tyrosine 78 phosphorylation and tumor growth in vivo. Taken together, inhibiting Jak2-mediated tyrosine 78 phosphorylation could provide a viable therapy for medulloblastoma.
format Online
Article
Text
id pubmed-5736349
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-57363492017-12-21 Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth Klisch, Tiemo J Vainshtein, Anna Patel, Akash J Zoghbi, Huda Y eLife Cancer Biology Treatment for medulloblastoma, the most common malignant brain tumor in children, remains limited to surgical resection, radiation, and traditional chemotherapy; with long-term survival as low as 50–60% for Sonic Hedgehog (Shh)-type medulloblastoma. We have shown that the transcription factor Atonal homologue 1 (Atoh1) is required for Shh-type medulloblastoma development in mice. To determine whether reducing either Atoh1 levels or activity in tumors after their development is beneficial, we studied Atoh1 dosage and modifications in Shh-type medulloblastoma. Heterozygosity of Atoh1 reduced tumor occurrence and prolonged survival. We discovered tyrosine 78 of Atoh1 is phosphorylated by a Jak2-mediated pathway only in tumor-initiating cells and in human SHH-type medulloblastoma. Phosphorylation of tyrosine 78 stabilizes Atoh1, increases Atoh1’s transcriptional activity, and is independent of canonical Jak2 signaling. Importantly, inhibition of Jak2 impairs tyrosine 78 phosphorylation and tumor growth in vivo. Taken together, inhibiting Jak2-mediated tyrosine 78 phosphorylation could provide a viable therapy for medulloblastoma. eLife Sciences Publications, Ltd 2017-11-23 /pmc/articles/PMC5736349/ /pubmed/29168692 http://dx.doi.org/10.7554/eLife.31181 Text en © 2017, Klisch et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Klisch, Tiemo J
Vainshtein, Anna
Patel, Akash J
Zoghbi, Huda Y
Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth
title Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth
title_full Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth
title_fullStr Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth
title_full_unstemmed Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth
title_short Jak2-mediated phosphorylation of Atoh1 is critical for medulloblastoma growth
title_sort jak2-mediated phosphorylation of atoh1 is critical for medulloblastoma growth
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736349/
https://www.ncbi.nlm.nih.gov/pubmed/29168692
http://dx.doi.org/10.7554/eLife.31181
work_keys_str_mv AT klischtiemoj jak2mediatedphosphorylationofatoh1iscriticalformedulloblastomagrowth
AT vainshteinanna jak2mediatedphosphorylationofatoh1iscriticalformedulloblastomagrowth
AT patelakashj jak2mediatedphosphorylationofatoh1iscriticalformedulloblastomagrowth
AT zoghbihuday jak2mediatedphosphorylationofatoh1iscriticalformedulloblastomagrowth