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Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway
Constitutive activation of the Rearranged during Transfection (RET) proto-oncogene leads to the development of MEN2A medullary thyroid cancer (MTC). The relatively clear genotype/phenotype relationship seen with RET mutations and the development of MEN2A is unusual in the fact that a single gene act...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466258/ https://www.ncbi.nlm.nih.gov/pubmed/26065416 http://dx.doi.org/10.1371/journal.pone.0127943 |
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author | Burdine, Lyle J. Burdine, Marie Schluterman Moreland, Linley Fogel, Brad Orr, Lisa M. James, Jennifer Turnage, Richard H. Tackett, Alan J. |
author_facet | Burdine, Lyle J. Burdine, Marie Schluterman Moreland, Linley Fogel, Brad Orr, Lisa M. James, Jennifer Turnage, Richard H. Tackett, Alan J. |
author_sort | Burdine, Lyle J. |
collection | PubMed |
description | Constitutive activation of the Rearranged during Transfection (RET) proto-oncogene leads to the development of MEN2A medullary thyroid cancer (MTC). The relatively clear genotype/phenotype relationship seen with RET mutations and the development of MEN2A is unusual in the fact that a single gene activity can drive the progression towards metastatic disease. Despite knowing the oncogene responsible for MEN2A, MTC, like most tumors of neural crest origin, remains largely resistant to chemotherapy. Constitutive activation of RET in a SK-N-MC cell line model reduces cell sensitivity to chemotherapy. In an attempt to identify components of the machinery responsible for the observed RET induced chemoresistance, we performed a proteomic screen of histones and associated proteins in cells with a constitutively active RET signaling pathway. The proteomic approach identified DNA-PKcs, a DNA damage response protein, as a target of the RET signaling pathway. Active DNA-PKcs, which is phosphorylated at site serine 2056 and localized to chromatin, was elevated within our model. Treatment with the RET inhibitor RPI-1 significantly reduced s2056 phosphorylation in RET cells as well as in a human medullary thyroid cancer cell line. Additionally, inhibition of DNA-PKcs activity diminished the chemoresistance observed in both cell lines. Importantly, we show that activated DNA-PKcs is elevated in medullary thyroid tumor samples and that expression correlates with expression of RET in thyroid tumors. These results highlight one mechanism by which RET signaling likely primes cells for rapid response to DNA damage and suggests DNA-PKcs as an additional target in MTC. |
format | Online Article Text |
id | pubmed-4466258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44662582015-06-25 Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway Burdine, Lyle J. Burdine, Marie Schluterman Moreland, Linley Fogel, Brad Orr, Lisa M. James, Jennifer Turnage, Richard H. Tackett, Alan J. PLoS One Research Article Constitutive activation of the Rearranged during Transfection (RET) proto-oncogene leads to the development of MEN2A medullary thyroid cancer (MTC). The relatively clear genotype/phenotype relationship seen with RET mutations and the development of MEN2A is unusual in the fact that a single gene activity can drive the progression towards metastatic disease. Despite knowing the oncogene responsible for MEN2A, MTC, like most tumors of neural crest origin, remains largely resistant to chemotherapy. Constitutive activation of RET in a SK-N-MC cell line model reduces cell sensitivity to chemotherapy. In an attempt to identify components of the machinery responsible for the observed RET induced chemoresistance, we performed a proteomic screen of histones and associated proteins in cells with a constitutively active RET signaling pathway. The proteomic approach identified DNA-PKcs, a DNA damage response protein, as a target of the RET signaling pathway. Active DNA-PKcs, which is phosphorylated at site serine 2056 and localized to chromatin, was elevated within our model. Treatment with the RET inhibitor RPI-1 significantly reduced s2056 phosphorylation in RET cells as well as in a human medullary thyroid cancer cell line. Additionally, inhibition of DNA-PKcs activity diminished the chemoresistance observed in both cell lines. Importantly, we show that activated DNA-PKcs is elevated in medullary thyroid tumor samples and that expression correlates with expression of RET in thyroid tumors. These results highlight one mechanism by which RET signaling likely primes cells for rapid response to DNA damage and suggests DNA-PKcs as an additional target in MTC. Public Library of Science 2015-06-11 /pmc/articles/PMC4466258/ /pubmed/26065416 http://dx.doi.org/10.1371/journal.pone.0127943 Text en © 2015 Burdine 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Burdine, Lyle J. Burdine, Marie Schluterman Moreland, Linley Fogel, Brad Orr, Lisa M. James, Jennifer Turnage, Richard H. Tackett, Alan J. Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway |
title | Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway |
title_full | Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway |
title_fullStr | Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway |
title_full_unstemmed | Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway |
title_short | Proteomic Identification of DNA-PK Involvement within the RET Signaling Pathway |
title_sort | proteomic identification of dna-pk involvement within the ret signaling pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466258/ https://www.ncbi.nlm.nih.gov/pubmed/26065416 http://dx.doi.org/10.1371/journal.pone.0127943 |
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