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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2017
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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 |
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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 |
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