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Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells

Contrary to cell cycle–associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stim...

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Autores principales: Lindqvist, Julia, Imanishi, Susumu Y., Torvaldson, Elin, Malinen, Marjo, Remes, Mika, Örn, Fanny, Palvimo, Jorma J., Eriksson, John E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472009/
https://www.ncbi.nlm.nih.gov/pubmed/25851605
http://dx.doi.org/10.1091/mbc.E14-12-1634
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author Lindqvist, Julia
Imanishi, Susumu Y.
Torvaldson, Elin
Malinen, Marjo
Remes, Mika
Örn, Fanny
Palvimo, Jorma J.
Eriksson, John E.
author_facet Lindqvist, Julia
Imanishi, Susumu Y.
Torvaldson, Elin
Malinen, Marjo
Remes, Mika
Örn, Fanny
Palvimo, Jorma J.
Eriksson, John E.
author_sort Lindqvist, Julia
collection PubMed
description Contrary to cell cycle–associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-depdent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks.
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spelling pubmed-44720092015-08-16 Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells Lindqvist, Julia Imanishi, Susumu Y. Torvaldson, Elin Malinen, Marjo Remes, Mika Örn, Fanny Palvimo, Jorma J. Eriksson, John E. Mol Biol Cell Articles Contrary to cell cycle–associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-depdent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks. The American Society for Cell Biology 2015-06-01 /pmc/articles/PMC4472009/ /pubmed/25851605 http://dx.doi.org/10.1091/mbc.E14-12-1634 Text en © 2015 Lindqvist et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Lindqvist, Julia
Imanishi, Susumu Y.
Torvaldson, Elin
Malinen, Marjo
Remes, Mika
Örn, Fanny
Palvimo, Jorma J.
Eriksson, John E.
Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells
title Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells
title_full Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells
title_fullStr Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells
title_full_unstemmed Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells
title_short Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells
title_sort cyclin-dependent kinase 5 acts as a critical determinant of akt-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472009/
https://www.ncbi.nlm.nih.gov/pubmed/25851605
http://dx.doi.org/10.1091/mbc.E14-12-1634
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