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Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions
The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary dr...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193403/ https://www.ncbi.nlm.nih.gov/pubmed/28030567 http://dx.doi.org/10.1371/journal.pone.0168031 |
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author | Urman, Nicole M. Mirza, Amar Atwood, Scott X. Whitson, Ramon J. Sarin, Kavita Y. Tang, Jean Y. Oro, Anthony E. |
author_facet | Urman, Nicole M. Mirza, Amar Atwood, Scott X. Whitson, Ramon J. Sarin, Kavita Y. Tang, Jean Y. Oro, Anthony E. |
author_sort | Urman, Nicole M. |
collection | PubMed |
description | The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU’s role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise. |
format | Online Article Text |
id | pubmed-5193403 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-51934032017-01-19 Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions Urman, Nicole M. Mirza, Amar Atwood, Scott X. Whitson, Ramon J. Sarin, Kavita Y. Tang, Jean Y. Oro, Anthony E. PLoS One Research Article The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU’s role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise. Public Library of Science 2016-12-28 /pmc/articles/PMC5193403/ /pubmed/28030567 http://dx.doi.org/10.1371/journal.pone.0168031 Text en © 2016 Urman et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Urman, Nicole M. Mirza, Amar Atwood, Scott X. Whitson, Ramon J. Sarin, Kavita Y. Tang, Jean Y. Oro, Anthony E. Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions |
title | Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions |
title_full | Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions |
title_fullStr | Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions |
title_full_unstemmed | Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions |
title_short | Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions |
title_sort | tumor-derived suppressor of fused mutations reveal hedgehog pathway interactions |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193403/ https://www.ncbi.nlm.nih.gov/pubmed/28030567 http://dx.doi.org/10.1371/journal.pone.0168031 |
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