Cargando…

Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer

Regulation of the androgen receptor (AR) is critical to prostate cancer (PCa) development; therefore, AR is the first line therapeutic target for disseminated tumors. Cell cycle dependent accumulation of cyclin D1 negatively modulates the transcriptional regulation of the AR through discrete, CDK4-i...

Descripción completa

Detalles Bibliográficos
Autores principales: Schiewer, Matthew J., Morey, Lisa M., Burd, Craig J., Liu, Yuhong, Merry, Diane E., Ho, Shuk-Mei, Knudsen, Karen E.
Formato: Texto
Lenguaje:English
Publicado: 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852245/
https://www.ncbi.nlm.nih.gov/pubmed/19079343
http://dx.doi.org/10.1038/onc.2008.446
_version_ 1782179926903881728
author Schiewer, Matthew J.
Morey, Lisa M.
Burd, Craig J.
Liu, Yuhong
Merry, Diane E.
Ho, Shuk-Mei
Knudsen, Karen E.
author_facet Schiewer, Matthew J.
Morey, Lisa M.
Burd, Craig J.
Liu, Yuhong
Merry, Diane E.
Ho, Shuk-Mei
Knudsen, Karen E.
author_sort Schiewer, Matthew J.
collection PubMed
description Regulation of the androgen receptor (AR) is critical to prostate cancer (PCa) development; therefore, AR is the first line therapeutic target for disseminated tumors. Cell cycle dependent accumulation of cyclin D1 negatively modulates the transcriptional regulation of the AR through discrete, CDK4-independent mechanisms. The transcriptional co-repressor function of cyclin D1 resides within a defined motif termed ther repressor domain (RD), and it was hypothesized that this motif could be utilized as a platform to develop new strategies for blocking AR function. Here, we demonstrate that expression of the RD peptide is sufficient to disrupt AR transcriptional activation of multiple, prostate-specific AR target genes. Importantly, these actions are sufficient to specifically inhibit S-phase progression in AR-positive PCa cells, but not in AR-negative cells or tested AR-positive cells of other lineages. As expected, impaired cell cycle progression resulted in a suppression of cell doubling. Additionally, cell death was observed in AR-positive cells that maintain androgen dependence and in a subset of castrate-resistant PCa cells, dependent on Akt activation status. Lastly, the ability of RD to cooperate with existing hormone therapies was examined, which revealed that RD enhanced the cellular response to an AR antagonist. Together, these data demonstrate that RD is sufficient to disrupt AR-dependent transcriptional and proliferative responses in PCa, and can enhance efficacy of AR antagonists, thus establishing the impetus for development of RD-based mimetics.
format Text
id pubmed-2852245
institution National Center for Biotechnology Information
language English
publishDate 2008
record_format MEDLINE/PubMed
spelling pubmed-28522452010-04-09 Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer Schiewer, Matthew J. Morey, Lisa M. Burd, Craig J. Liu, Yuhong Merry, Diane E. Ho, Shuk-Mei Knudsen, Karen E. Oncogene Article Regulation of the androgen receptor (AR) is critical to prostate cancer (PCa) development; therefore, AR is the first line therapeutic target for disseminated tumors. Cell cycle dependent accumulation of cyclin D1 negatively modulates the transcriptional regulation of the AR through discrete, CDK4-independent mechanisms. The transcriptional co-repressor function of cyclin D1 resides within a defined motif termed ther repressor domain (RD), and it was hypothesized that this motif could be utilized as a platform to develop new strategies for blocking AR function. Here, we demonstrate that expression of the RD peptide is sufficient to disrupt AR transcriptional activation of multiple, prostate-specific AR target genes. Importantly, these actions are sufficient to specifically inhibit S-phase progression in AR-positive PCa cells, but not in AR-negative cells or tested AR-positive cells of other lineages. As expected, impaired cell cycle progression resulted in a suppression of cell doubling. Additionally, cell death was observed in AR-positive cells that maintain androgen dependence and in a subset of castrate-resistant PCa cells, dependent on Akt activation status. Lastly, the ability of RD to cooperate with existing hormone therapies was examined, which revealed that RD enhanced the cellular response to an AR antagonist. Together, these data demonstrate that RD is sufficient to disrupt AR-dependent transcriptional and proliferative responses in PCa, and can enhance efficacy of AR antagonists, thus establishing the impetus for development of RD-based mimetics. 2008-12-15 2009-02-19 /pmc/articles/PMC2852245/ /pubmed/19079343 http://dx.doi.org/10.1038/onc.2008.446 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Schiewer, Matthew J.
Morey, Lisa M.
Burd, Craig J.
Liu, Yuhong
Merry, Diane E.
Ho, Shuk-Mei
Knudsen, Karen E.
Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
title Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
title_full Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
title_fullStr Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
title_full_unstemmed Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
title_short Cyclin D1 repressor domain mediates proliferation and survival in prostate cancer
title_sort cyclin d1 repressor domain mediates proliferation and survival in prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852245/
https://www.ncbi.nlm.nih.gov/pubmed/19079343
http://dx.doi.org/10.1038/onc.2008.446
work_keys_str_mv AT schiewermatthewj cyclind1repressordomainmediatesproliferationandsurvivalinprostatecancer
AT moreylisam cyclind1repressordomainmediatesproliferationandsurvivalinprostatecancer
AT burdcraigj cyclind1repressordomainmediatesproliferationandsurvivalinprostatecancer
AT liuyuhong cyclind1repressordomainmediatesproliferationandsurvivalinprostatecancer
AT merrydianee cyclind1repressordomainmediatesproliferationandsurvivalinprostatecancer
AT hoshukmei cyclind1repressordomainmediatesproliferationandsurvivalinprostatecancer
AT knudsenkarene cyclind1repressordomainmediatesproliferationandsurvivalinprostatecancer