Cargando…

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)...

Descripción completa

Detalles Bibliográficos
Autores principales: Ta, Huy Q, Dworak, Natalia, Ivey, Melissa L, Roller, Devin G, Gioeli, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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
_version_ 1783554598395445248
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
work_keys_str_mv AT tahuyq arphosphorylationandchk2kinaseactivityregulatesirstabilizedarchk2interactionandprostatecancersurvival
AT dworaknatalia arphosphorylationandchk2kinaseactivityregulatesirstabilizedarchk2interactionandprostatecancersurvival
AT iveymelissal arphosphorylationandchk2kinaseactivityregulatesirstabilizedarchk2interactionandprostatecancersurvival
AT rollerdeving arphosphorylationandchk2kinaseactivityregulatesirstabilizedarchk2interactionandprostatecancersurvival
AT gioelidaniel arphosphorylationandchk2kinaseactivityregulatesirstabilizedarchk2interactionandprostatecancersurvival