Checkpoint kinase 2 regulates prostate cancer cell growth through physical interactions with the androgen receptor
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...
Saved in:
Published in | bioRxiv |
---|---|
Main Authors | , , , , |
Format | Paper |
Language | English |
Published |
Cold Spring Harbor
Cold Spring Harbor Laboratory Press
04.05.2020
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Abstract | 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 suppression of PCa cell growth. CHK2 mutation or loss of expression thereby leads to increased AR transcriptional activity and survival in response to DNA damage. Competing Interest Statement The authors have declared no competing interest. Footnotes * The paper has been substantially revised as part of a peer review process. Previously included data has been revised with new data, and entirely new data is now included. |
---|---|
AbstractList | 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 suppression of PCa cell growth. CHK2 mutation or loss of expression thereby leads to increased AR transcriptional activity and survival in response to DNA damage. Competing Interest Statement The authors have declared no competing interest. Footnotes * The paper has been substantially revised as part of a peer review process. Previously included data has been revised with new data, and entirely new data is now included. |
Author | Roller, Devin G Ivey, Melissa L Gioeli, Daniel Dworak, Natalia Ta, Huy Q |
Author_xml | – sequence: 1 givenname: Huy surname: Ta middlename: Q fullname: Ta, Huy Q – sequence: 2 givenname: Natalia surname: Dworak fullname: Dworak, Natalia – sequence: 3 givenname: Melissa surname: Ivey middlename: L fullname: Ivey, Melissa L – sequence: 4 givenname: Devin surname: Roller middlename: G fullname: Roller, Devin G – sequence: 5 givenname: Daniel surname: Gioeli fullname: Gioeli, Daniel |
BookMark | eNqNjUsKAjEQRLPQhd8zNLhWJ_G_FsUDuJcQ20k0dI-dDOLtDeIBXFVBPV71VYeYUKmxrmZaV3q-We300vSU7D26R8OBMjwC2YRgQLBuo82YoBFOuTRwlhwKOIwRauFX9pC9cFt7aPw7BWcjFAeKdTkwJXiFL4Jg6SpcIxWrwyazDFX3ZmPC0S8HanI8nPenaTl7tpjy5c6tUJkuxmyX21W1W5vFf9QHhn9MIg |
ContentType | Paper |
Copyright | 2020. Notwithstanding the ProQuest Terms and conditions, you may use this content in accordance with the associated terms available at https://www.biorxiv.org/content/10.1101/759142v2 |
Copyright_xml | – notice: 2020. Notwithstanding the ProQuest Terms and conditions, you may use this content in accordance with the associated terms available at https://www.biorxiv.org/content/10.1101/759142v2 |
DBID | 8FE 8FH AAFGM AAMXL ABOIG ABUWG ADZZV AFKRA AFLLJ AFOLM AGAJT AQTIP AZQEC BBNVY BENPR BHPHI CCPQU DWQXO GNUQQ HCIFZ LK8 M7P PIMPY PQCXX PQEST PQQKQ PQUKI PRINS |
DOI | 10.1101/759142 |
DatabaseName | ProQuest SciTech Collection ProQuest Natural Science Collection ProQuest Central Korea - hybrid linking Natural Science Collection - hybrid linking Biological Science Collection - hybrid linking ProQuest Central (Alumni) ProQuest Central (Alumni) - hybrid linking ProQuest Central UK/Ireland SciTech Premium Collection - hybrid linking ProQuest Central Student - hybrid linking ProQuest Central Essentials - hybrid linking ProQuest Women's & Gender Studies - hybrid linking ProQuest Central Essentials Biological Science Collection AUTh Library subscriptions: ProQuest Central ProQuest Natural Science Collection ProQuest One Community College ProQuest Central ProQuest Central Student SciTech Premium Collection Biological Sciences Biological Science Database ProQuest - Publicly Available Content Database ProQuest Central - hybrid linking ProQuest One Academic Eastern Edition (DO NOT USE) ProQuest One Academic ProQuest One Academic UKI Edition ProQuest Central China |
DatabaseTitle | Publicly Available Content Database ProQuest Central Student ProQuest Biological Science Collection ProQuest Central Essentials ProQuest One Academic Eastern Edition ProQuest Central (Alumni Edition) SciTech Premium Collection ProQuest One Community College ProQuest Natural Science Collection Biological Science Database ProQuest SciTech Collection ProQuest Central China ProQuest Central ProQuest One Academic UKI Edition Natural Science Collection ProQuest Central Korea Biological Science Collection ProQuest One Academic |
DatabaseTitleList | Publicly Available Content Database |
Database_xml | – sequence: 1 dbid: BENPR name: AUTh Library subscriptions: ProQuest Central url: https://www.proquest.com/central sourceTypes: Aggregation Database |
DeliveryMethod | fulltext_linktorsrc |
Genre | Working Paper/Pre-Print |
GroupedDBID | 8FE 8FH ABUWG AFKRA AZQEC BBNVY BENPR BHPHI CCPQU DWQXO GNUQQ HCIFZ LK8 M7P PIMPY PQEST PQQKQ PQUKI PRINS |
ID | FETCH-proquest_journals_22848509623 |
IEDL.DBID | BENPR |
IngestDate | Thu Oct 10 22:15:37 EDT 2024 |
IsDoiOpenAccess | true |
IsOpenAccess | true |
IsPeerReviewed | false |
IsScholarly | false |
Language | English |
LinkModel | DirectLink |
MergedId | FETCHMERGED-proquest_journals_22848509623 |
OpenAccessLink | https://www.proquest.com/docview/2284850962?pq-origsite=%requestingapplication% |
PQID | 2284850962 |
PQPubID | 2050091 |
ParticipantIDs | proquest_journals_2284850962 |
PublicationCentury | 2000 |
PublicationDate | 20200504 |
PublicationDateYYYYMMDD | 2020-05-04 |
PublicationDate_xml | – month: 05 year: 2020 text: 20200504 day: 04 |
PublicationDecade | 2020 |
PublicationPlace | Cold Spring Harbor |
PublicationPlace_xml | – name: Cold Spring Harbor |
PublicationTitle | bioRxiv |
PublicationYear | 2020 |
Publisher | Cold Spring Harbor Laboratory Press |
Publisher_xml | – name: Cold Spring Harbor Laboratory Press |
Score | 3.2717729 |
Snippet | We have previously demonstrated that checkpoint kinase 2 (CHK2) is a critical negative regulator of androgen receptor (AR) transcriptional activity, prostate... |
SourceID | proquest |
SourceType | Aggregation Database |
SubjectTerms | Androgen receptors Androgens Cell growth CHK2 protein DNA damage Ionizing radiation Kinases Phosphorylation Prostate cancer Transcription |
Title | Checkpoint kinase 2 regulates prostate cancer cell growth through physical interactions with the androgen receptor |
URI | https://www.proquest.com/docview/2284850962 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1NSwMxEB20e_GmqPhRZUCvS3djtqknwdJSPJQiCr2V2U1qS2F3za7_35k2xYPQWyAhXzv7HplM5gE8GkWkEtKxTdQy1tb2-ZfSSbxMM-OsspKkSqItpv3Jp36bZ_PgcGtCWOUeE7dAbatCfOQ9xTg6kFwl6qX-jkU1Sm5Xg4TGMUQq1XJNG72OprP3ICLE5tYzGY-t_iHtlj7GpxDNqHb-DI5ceQ5-uHLFpq7WZYubdck0ggr9ThPeNVjLOwwuYSEfxKO41vGLT8vtCoOqDtZhd1GyPfjd24QGxafKTRySZCFgy-BeJWql8hfwMB59DCfxfnqLYEPN4m_FT5fQKavSXQEydhV9ooSYW3WRE5lnyg2ZtGCez1J7Dd1DPd0crr6FEyXnSQno013otP7H3THptvl92NlfQ0yMzQ |
link.rule.ids | 786,790,21416,27956,33777,43838 |
linkProvider | ProQuest |
linkToHtml | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwfV1NS8NAEB00OehNUfGj6oBeQ5M1H_UkWFqi1lCkQm9lk93aUkjiJv5_Z9otHoTeAgmb3c3kPXZ29j2A-0RIKXwZesoXcy9UKqZfKvS9eRAlWgnFIlVcbZHF6Wf4Oo2mNuHW2LLKLSaugVpVBefIu4JwtMdaJeKp_vbYNYp3V62Fxj64LLnZc8B9HmTjD2siROHWTSJ6t_iHtGv6GB6BO5a1Nsewp8sTMP2FLlZ1tSxbXC1LohEUaDae8LrBms9h0BUW_EEMcmodv2i13C7QuupgbWcXWe3BbM4mNMg5VXpEo2QVAooMapWrVipzCnfDwaSfetvuzWwMNbO_ET-cgVNWpT4HJOwqYil9SdwaFrmUyaPME5kEBfF8FKgL6Oxq6XL37Vs4SCfvo9noJXu7gkPBa0su7gs74LTmR18TAbf5jZ3lXw4Lj8M |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Checkpoint+kinase+2+regulates+prostate+cancer+cell+growth+through+physical+interactions+with+the+androgen+receptor&rft.jtitle=bioRxiv&rft.au=Ta%2C+Huy+Q&rft.au=Dworak%2C+Natalia&rft.au=Ivey%2C+Melissa+L&rft.au=Roller%2C+Devin+G&rft.date=2020-05-04&rft.pub=Cold+Spring+Harbor+Laboratory+Press&rft_id=info:doi/10.1101%2F759142 |