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AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival
We have previously demonstrated that checkpoint kinase 2 (CHK2) is a critical negative regulator of androgen receptor (AR) transcriptional activity, prostate cancer (PCa) cell growth, and androgen sensitivity. We have now uncovered that the AR directly interacts with CHK2 and ionizing radiation (IR)...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338052/ https://www.ncbi.nlm.nih.gov/pubmed/32579110 http://dx.doi.org/10.7554/eLife.51378 |
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author | Ta, Huy Q Dworak, Natalia Ivey, Melissa L Roller, Devin G Gioeli, Daniel |
author_facet | Ta, Huy Q Dworak, Natalia Ivey, Melissa L Roller, Devin G Gioeli, Daniel |
author_sort | Ta, Huy Q |
collection | PubMed |
description | We have previously demonstrated that checkpoint kinase 2 (CHK2) is a critical negative regulator of androgen receptor (AR) transcriptional activity, prostate cancer (PCa) cell growth, and androgen sensitivity. We have now uncovered that the AR directly interacts with CHK2 and ionizing radiation (IR) increases this interaction. This IR-induced increase in AR–CHK2 interactions requires AR phosphorylation and CHK2 kinase activity. PCa associated CHK2 mutants with impaired kinase activity reduced IR-induced AR–CHK2 interactions. The destabilization of AR – CHK2 interactions induced by CHK2 variants impairs CHK2 negative regulation of cell growth. CHK2 depletion increases transcription of DNAPK and RAD54, increases clonogenic survival, and increases resolution of DNA double strand breaks. The data support a model where CHK2 sequesters the AR through direct binding decreasing AR transcription and suppressing PCa cell growth. CHK2 mutation or loss of expression thereby leads to increased AR transcriptional activity and survival in response to DNA damage. |
format | Online Article Text |
id | pubmed-7338052 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-73380522020-07-13 AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival Ta, Huy Q Dworak, Natalia Ivey, Melissa L Roller, Devin G Gioeli, Daniel eLife Biochemistry and Chemical Biology We have previously demonstrated that checkpoint kinase 2 (CHK2) is a critical negative regulator of androgen receptor (AR) transcriptional activity, prostate cancer (PCa) cell growth, and androgen sensitivity. We have now uncovered that the AR directly interacts with CHK2 and ionizing radiation (IR) increases this interaction. This IR-induced increase in AR–CHK2 interactions requires AR phosphorylation and CHK2 kinase activity. PCa associated CHK2 mutants with impaired kinase activity reduced IR-induced AR–CHK2 interactions. The destabilization of AR – CHK2 interactions induced by CHK2 variants impairs CHK2 negative regulation of cell growth. CHK2 depletion increases transcription of DNAPK and RAD54, increases clonogenic survival, and increases resolution of DNA double strand breaks. The data support a model where CHK2 sequesters the AR through direct binding decreasing AR transcription and suppressing PCa cell growth. CHK2 mutation or loss of expression thereby leads to increased AR transcriptional activity and survival in response to DNA damage. eLife Sciences Publications, Ltd 2020-06-24 /pmc/articles/PMC7338052/ /pubmed/32579110 http://dx.doi.org/10.7554/eLife.51378 Text en © 2020, Ta 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 | Biochemistry and Chemical Biology Ta, Huy Q Dworak, Natalia Ivey, Melissa L Roller, Devin G Gioeli, Daniel AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival |
title | AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival |
title_full | AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival |
title_fullStr | AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival |
title_full_unstemmed | AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival |
title_short | AR phosphorylation and CHK2 kinase activity regulates IR-stabilized AR–CHK2 interaction and prostate cancer survival |
title_sort | ar phosphorylation and chk2 kinase activity regulates ir-stabilized ar–chk2 interaction and prostate cancer survival |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338052/ https://www.ncbi.nlm.nih.gov/pubmed/32579110 http://dx.doi.org/10.7554/eLife.51378 |
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