LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.

<h4>Background</h4>Nuclear factor κB (NF-κB)-mediated pathways have been widely implicated in cell survival, development and tumor progression. Although the molecular events of determining NF-κB translocation from cytoplasm to nucleus have been extensively documented, the regulatory mech...

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Autores principales:	Zhiqiang Wu, Yazhuo Li, Xiaolei Li, Dongdong Ti, Yali Zhao, Yiling Si, Qian Mei, Po Zhao, Xiaobing Fu, Weidong Han
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/39e9a7a615694dcd9885f218fba62899
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spelling	oai:doaj.org-article:39e9a7a615694dcd9885f218fba628992021-11-18T06:56:27ZLRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.1932-620310.1371/journal.pone.0018157https://doaj.org/article/39e9a7a615694dcd9885f218fba628992011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21483817/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Nuclear factor κB (NF-κB)-mediated pathways have been widely implicated in cell survival, development and tumor progression. Although the molecular events of determining NF-κB translocation from cytoplasm to nucleus have been extensively documented, the regulatory mechanisms of NF-κB activity inside the nucleus are still poorly understood. Being a special member of macro domain proteins, LRP16 was previously identified as a coactivator of both estrogen receptor and androgen receptor, and as an interactor of NF-κB coactivator UXT. Here, we investigated the regulatory role of LRP16 on NF-κB activation.<h4>Methodology</h4>GST pull-down and coimmunoprecipitation (CoIP) assays assessed protein-protein interactions. The functional activity of NF-κB was assessed by luciferase assays, changes in expression of its target genes, and its DNA binding ability. Annexin V staining and flow cytometry analysis were used to evaluate cell apoptosis. Immunohistochemical staining of LRP16 and enzyme-linked immunosorbent assay-based evaluation of active NF-κB were performed on primary human gastric carcinoma samples.<h4>Results</h4>We demonstrate that LRP16 integrates into NF-κB transcriptional complex through associating with its p65 component. RNA interference knockdown of the endogenous LRP16 in cells leads to impaired NF-κB activity and significantly attenuated NF-κB-dependent gene expression. Mechanistic analysis revealed that knockdown of LRP16 did not affect tumor necrosis factor α (TNF-α)-induced nuclear translocation of NF-κB, but blunted the formation or stabilization of functional NF-κB/p300/CREB-binding protein transcription complex in the nucleus. In addition, knockdown of LRP16 also sensitizes cells to apoptosis induced by TNF-α. Finally, a positive link between LRP16 expression intensity in nuclei of tumor cells and NF-κB activity was preliminarily established in human gastric carcinoma specimens.<h4>Conclusions</h4>Our findings not only indicate that LRP16 is a crucial regulator for NF-κB activation inside the nucleus, but also suggest that LRP16 may be an important contributor to the aberrant activation of NF-κB in tumors.Zhiqiang WuYazhuo LiXiaolei LiDongdong TiYali ZhaoYiling SiQian MeiPo ZhaoXiaobing FuWeidong HanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 3, p e18157 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zhiqiang Wu Yazhuo Li Xiaolei Li Dongdong Ti Yali Zhao Yiling Si Qian Mei Po Zhao Xiaobing Fu Weidong Han LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.
description	<h4>Background</h4>Nuclear factor κB (NF-κB)-mediated pathways have been widely implicated in cell survival, development and tumor progression. Although the molecular events of determining NF-κB translocation from cytoplasm to nucleus have been extensively documented, the regulatory mechanisms of NF-κB activity inside the nucleus are still poorly understood. Being a special member of macro domain proteins, LRP16 was previously identified as a coactivator of both estrogen receptor and androgen receptor, and as an interactor of NF-κB coactivator UXT. Here, we investigated the regulatory role of LRP16 on NF-κB activation.<h4>Methodology</h4>GST pull-down and coimmunoprecipitation (CoIP) assays assessed protein-protein interactions. The functional activity of NF-κB was assessed by luciferase assays, changes in expression of its target genes, and its DNA binding ability. Annexin V staining and flow cytometry analysis were used to evaluate cell apoptosis. Immunohistochemical staining of LRP16 and enzyme-linked immunosorbent assay-based evaluation of active NF-κB were performed on primary human gastric carcinoma samples.<h4>Results</h4>We demonstrate that LRP16 integrates into NF-κB transcriptional complex through associating with its p65 component. RNA interference knockdown of the endogenous LRP16 in cells leads to impaired NF-κB activity and significantly attenuated NF-κB-dependent gene expression. Mechanistic analysis revealed that knockdown of LRP16 did not affect tumor necrosis factor α (TNF-α)-induced nuclear translocation of NF-κB, but blunted the formation or stabilization of functional NF-κB/p300/CREB-binding protein transcription complex in the nucleus. In addition, knockdown of LRP16 also sensitizes cells to apoptosis induced by TNF-α. Finally, a positive link between LRP16 expression intensity in nuclei of tumor cells and NF-κB activity was preliminarily established in human gastric carcinoma specimens.<h4>Conclusions</h4>Our findings not only indicate that LRP16 is a crucial regulator for NF-κB activation inside the nucleus, but also suggest that LRP16 may be an important contributor to the aberrant activation of NF-κB in tumors.
format	article
author	Zhiqiang Wu Yazhuo Li Xiaolei Li Dongdong Ti Yali Zhao Yiling Si Qian Mei Po Zhao Xiaobing Fu Weidong Han
author_facet	Zhiqiang Wu Yazhuo Li Xiaolei Li Dongdong Ti Yali Zhao Yiling Si Qian Mei Po Zhao Xiaobing Fu Weidong Han
author_sort	Zhiqiang Wu
title	LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.
title_short	LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.
title_full	LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.
title_fullStr	LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.
title_full_unstemmed	LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.
title_sort	lrp16 integrates into nf-κb transcriptional complex and is required for its functional activation.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/39e9a7a615694dcd9885f218fba62899
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LRP16 integrates into NF-κB transcriptional complex and is required for its functional activation.

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