$Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer$

Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer

Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the androgen receptor at numerous sites and the functional consequences of AR phosphorylation are o...

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Main Authors:	Ha, Susan, Iqbal, Niloy J., Mita, Paolo, Ruoff, Rachel, Gerald, William L., Lepor, Herbert, Taneja, Samir S., Lee, Peng, Melamed, Jonathan, Garabedian, Michael J., Logan, Susan K.
Format:	Online
Language:	English
Published:	2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527659/

id	pubmed-3527659
recordtype	oai_dc
spelling	pubmed-35276592014-02-22 Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer Ha, Susan Iqbal, Niloy J. Mita, Paolo Ruoff, Rachel Gerald, William L. Lepor, Herbert Taneja, Samir S. Lee, Peng Melamed, Jonathan Garabedian, Michael J. Logan, Susan K. Article Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the androgen receptor at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine to alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand independent manner and cell type specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl, and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild type AR, but not S213A mutant AR. Androgen mediated transcription of endogenous PSA, Nkx3.1, and IGFBP5 was also decreased in the presence of PIM1 whereas IL6, cyclin A1, and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer. 2012-09-17 2013-08-22 /pmc/articles/PMC3527659/ /pubmed/22986532 http://dx.doi.org/10.1038/onc.2012.412 Text en Users may view, print, copy, download and 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
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ha, Susan Iqbal, Niloy J. Mita, Paolo Ruoff, Rachel Gerald, William L. Lepor, Herbert Taneja, Samir S. Lee, Peng Melamed, Jonathan Garabedian, Michael J. Logan, Susan K.
spellingShingle	Ha, Susan Iqbal, Niloy J. Mita, Paolo Ruoff, Rachel Gerald, William L. Lepor, Herbert Taneja, Samir S. Lee, Peng Melamed, Jonathan Garabedian, Michael J. Logan, Susan K. Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer
author_facet	Ha, Susan Iqbal, Niloy J. Mita, Paolo Ruoff, Rachel Gerald, William L. Lepor, Herbert Taneja, Samir S. Lee, Peng Melamed, Jonathan Garabedian, Michael J. Logan, Susan K.
author_sort	Ha, Susan
title	Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer
title_short	Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer
title_full	Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer
title_fullStr	Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer
title_full_unstemmed	Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer
title_sort	phosphorylation of the androgen receptor by pim1 in hormone refractory prostate cancer
description	Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the androgen receptor at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine to alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand independent manner and cell type specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl, and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild type AR, but not S213A mutant AR. Androgen mediated transcription of endogenous PSA, Nkx3.1, and IGFBP5 was also decreased in the presence of PIM1 whereas IL6, cyclin A1, and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527659/
_version_	1611942147880124416

Phosphorylation of the Androgen Receptor by PIM1 in Hormone Refractory Prostate Cancer

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