Cargando…
Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects
While many solid tumors are defined by the presence of a particular oncogene, the role that this oncogene plays in driving transformation through the acquisition of aneuploidy and overcoming growth arrest are often not known. Further, although aneuploidy is present in many solid tumors, it is not cl...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325330/ https://www.ncbi.nlm.nih.gov/pubmed/27588498 http://dx.doi.org/10.18632/oncotarget.11716 |
_version_ | 1782510359805952000 |
---|---|
author | Loupe, Jacob M. Miller, Patrick J. Bonner, Benjamin P. Maggi, Elaine C. Vijayaraghavan, Jyothi Zabaleta, Jovanny Taylor, Christopher M. Tsien, Fern Crabtree, Judy S. Hollenbach, Andrew D. |
author_facet | Loupe, Jacob M. Miller, Patrick J. Bonner, Benjamin P. Maggi, Elaine C. Vijayaraghavan, Jyothi Zabaleta, Jovanny Taylor, Christopher M. Tsien, Fern Crabtree, Judy S. Hollenbach, Andrew D. |
author_sort | Loupe, Jacob M. |
collection | PubMed |
description | While many solid tumors are defined by the presence of a particular oncogene, the role that this oncogene plays in driving transformation through the acquisition of aneuploidy and overcoming growth arrest are often not known. Further, although aneuploidy is present in many solid tumors, it is not clear whether it is the cause or effect of malignant transformation. The childhood sarcoma, Alveolar Rhabdomyosarcoma (ARMS), is primarily defined by the t(2;13)(q35;q14) translocation, creating the PAX3-FOXO1 fusion protein. It is unclear what role PAX3-FOXO1 plays in the initial stages of tumor development through the acquisition and persistence of aneuploidy. In this study we demonstrate that PAX3-FOXO1 serves as a driver mutation to initiate a cascade of mRNA and miRNA changes that ultimately reprogram proliferating myoblasts to induce the formation of ARMS. We present evidence that cells containing PAX3-FOXO1 have changes in the expression of mRNA and miRNA essential for maintaining proper chromosome number and structure thereby promoting aneuploidy. Further, we demonstrate that the presence of PAX3-FOXO1 alters the expression of growth factor related mRNA and miRNA, thereby overriding aneuploid-dependent growth arrest. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these changes. This is one of the first studies describing how an oncogene and post-translational modifications drive the development of a tumor through the acquisition and persistence of aneuploidy. This mechanism has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens. |
format | Online Article Text |
id | pubmed-5325330 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53253302017-03-23 Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects Loupe, Jacob M. Miller, Patrick J. Bonner, Benjamin P. Maggi, Elaine C. Vijayaraghavan, Jyothi Zabaleta, Jovanny Taylor, Christopher M. Tsien, Fern Crabtree, Judy S. Hollenbach, Andrew D. Oncotarget Priority Research Paper While many solid tumors are defined by the presence of a particular oncogene, the role that this oncogene plays in driving transformation through the acquisition of aneuploidy and overcoming growth arrest are often not known. Further, although aneuploidy is present in many solid tumors, it is not clear whether it is the cause or effect of malignant transformation. The childhood sarcoma, Alveolar Rhabdomyosarcoma (ARMS), is primarily defined by the t(2;13)(q35;q14) translocation, creating the PAX3-FOXO1 fusion protein. It is unclear what role PAX3-FOXO1 plays in the initial stages of tumor development through the acquisition and persistence of aneuploidy. In this study we demonstrate that PAX3-FOXO1 serves as a driver mutation to initiate a cascade of mRNA and miRNA changes that ultimately reprogram proliferating myoblasts to induce the formation of ARMS. We present evidence that cells containing PAX3-FOXO1 have changes in the expression of mRNA and miRNA essential for maintaining proper chromosome number and structure thereby promoting aneuploidy. Further, we demonstrate that the presence of PAX3-FOXO1 alters the expression of growth factor related mRNA and miRNA, thereby overriding aneuploid-dependent growth arrest. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these changes. This is one of the first studies describing how an oncogene and post-translational modifications drive the development of a tumor through the acquisition and persistence of aneuploidy. This mechanism has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens. Impact Journals LLC 2016-08-30 /pmc/articles/PMC5325330/ /pubmed/27588498 http://dx.doi.org/10.18632/oncotarget.11716 Text en Copyright: © 2016 Loupe et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Loupe, Jacob M. Miller, Patrick J. Bonner, Benjamin P. Maggi, Elaine C. Vijayaraghavan, Jyothi Zabaleta, Jovanny Taylor, Christopher M. Tsien, Fern Crabtree, Judy S. Hollenbach, Andrew D. Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects |
title | Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects |
title_full | Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects |
title_fullStr | Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects |
title_full_unstemmed | Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects |
title_short | Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects |
title_sort | acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325330/ https://www.ncbi.nlm.nih.gov/pubmed/27588498 http://dx.doi.org/10.18632/oncotarget.11716 |
work_keys_str_mv | AT loupejacobm acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT millerpatrickj acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT bonnerbenjaminp acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT maggielainec acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT vijayaraghavanjyothi acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT zabaletajovanny acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT taylorchristopherm acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT tsienfern acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT crabtreejudys acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects AT hollenbachandrewd acquisitionofanoncogenicfusionproteinservesasaninitialdrivingmutationbyinducinganeuploidyandoverridingproliferativedefects |