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A TRIP230-Retinoblastoma Protein Complex Regulates Hypoxia-Inducible Factor-1[alpha]-Mediated Transcription and Cancer Cell Invasion
Localized hypoxia in solid tumors activates transcriptional programs that promote the metastatic transformation of cells. Like hypoxia-inducible hyper-vascularization, loss of the retinoblastoma protein (Rb) is a trait common to advanced stages of tumor progression in many metastatic cancers. Howeve...
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Published in: | PloS one 2014-06, Vol.9 (6) |
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creator | Labrecque, Mark P Takhar, Mandeep K Jagdeo, Julienne M Tam, Kevin J Chiu, Christina Wang, Te-Yu Prefontaine, Gratien G Cox, Michael E Beischlag, Timothy V |
description | Localized hypoxia in solid tumors activates transcriptional programs that promote the metastatic transformation of cells. Like hypoxia-inducible hyper-vascularization, loss of the retinoblastoma protein (Rb) is a trait common to advanced stages of tumor progression in many metastatic cancers. However, no link between the role of Rb and hypoxia-driven metastatic processes has been established. We demonstrated that Rb is a key mediator of the hypoxic response mediated by HIF1[alpha]/[beta], the master regulator of the hypoxia response, and its essential co-activator, the thyroid hormone receptor/retinoblastoma-interacting protein (TRIP230). Furthermore, loss of Rb unmasks the full co-activation potential of TRIP230. Using small inhibitory RNA approaches in vivo, we established that Rb attenuates the normal physiological response to hypoxia by HIF1[alpha]. Notably, loss of Rb results in hypoxia-dependent biochemical changes that promote acquisition of an invasive phenotype in MCF7 breast cancer cells. In addition, Rb is present in HIF1[alpha]-ARNT/HIF1[beta] transcriptional complexes associated with TRIP230 as determined by co-immuno-precipitation, GST-pull-down and ChIP assays. These results demonstrate that Rb is a negative modulator of hypoxia-regulated transcription by virtue of its direct effects on the HIF1 complex. This work represents the first link between the functional ablation of Rb in tumor cells and HIF1[alpha]-dependent transcriptional activation and invasion. |
doi_str_mv | 10.1371/journal.pone.0099214 |
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Like hypoxia-inducible hyper-vascularization, loss of the retinoblastoma protein (Rb) is a trait common to advanced stages of tumor progression in many metastatic cancers. However, no link between the role of Rb and hypoxia-driven metastatic processes has been established. We demonstrated that Rb is a key mediator of the hypoxic response mediated by HIF1[alpha]/[beta], the master regulator of the hypoxia response, and its essential co-activator, the thyroid hormone receptor/retinoblastoma-interacting protein (TRIP230). Furthermore, loss of Rb unmasks the full co-activation potential of TRIP230. Using small inhibitory RNA approaches in vivo, we established that Rb attenuates the normal physiological response to hypoxia by HIF1[alpha]. Notably, loss of Rb results in hypoxia-dependent biochemical changes that promote acquisition of an invasive phenotype in MCF7 breast cancer cells. In addition, Rb is present in HIF1[alpha]-ARNT/HIF1[beta] transcriptional complexes associated with TRIP230 as determined by co-immuno-precipitation, GST-pull-down and ChIP assays. These results demonstrate that Rb is a negative modulator of hypoxia-regulated transcription by virtue of its direct effects on the HIF1 complex. This work represents the first link between the functional ablation of Rb in tumor cells and HIF1[alpha]-dependent transcriptional activation and invasion.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0099214</identifier><language>eng</language><publisher>Public Library of Science</publisher><subject>Cancer ; Physiological aspects ; Precipitation (Meteorology) ; Retinoblastoma ; RNA ; Transcription (Genetics)</subject><ispartof>PloS one, 2014-06, Vol.9 (6)</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Labrecque, Mark P</creatorcontrib><creatorcontrib>Takhar, Mandeep K</creatorcontrib><creatorcontrib>Jagdeo, Julienne M</creatorcontrib><creatorcontrib>Tam, Kevin J</creatorcontrib><creatorcontrib>Chiu, Christina</creatorcontrib><creatorcontrib>Wang, Te-Yu</creatorcontrib><creatorcontrib>Prefontaine, Gratien G</creatorcontrib><creatorcontrib>Cox, Michael E</creatorcontrib><creatorcontrib>Beischlag, Timothy V</creatorcontrib><title>A TRIP230-Retinoblastoma Protein Complex Regulates Hypoxia-Inducible Factor-1[alpha]-Mediated Transcription and Cancer Cell Invasion</title><title>PloS one</title><description>Localized hypoxia in solid tumors activates transcriptional programs that promote the metastatic transformation of cells. Like hypoxia-inducible hyper-vascularization, loss of the retinoblastoma protein (Rb) is a trait common to advanced stages of tumor progression in many metastatic cancers. However, no link between the role of Rb and hypoxia-driven metastatic processes has been established. We demonstrated that Rb is a key mediator of the hypoxic response mediated by HIF1[alpha]/[beta], the master regulator of the hypoxia response, and its essential co-activator, the thyroid hormone receptor/retinoblastoma-interacting protein (TRIP230). Furthermore, loss of Rb unmasks the full co-activation potential of TRIP230. Using small inhibitory RNA approaches in vivo, we established that Rb attenuates the normal physiological response to hypoxia by HIF1[alpha]. Notably, loss of Rb results in hypoxia-dependent biochemical changes that promote acquisition of an invasive phenotype in MCF7 breast cancer cells. In addition, Rb is present in HIF1[alpha]-ARNT/HIF1[beta] transcriptional complexes associated with TRIP230 as determined by co-immuno-precipitation, GST-pull-down and ChIP assays. These results demonstrate that Rb is a negative modulator of hypoxia-regulated transcription by virtue of its direct effects on the HIF1 complex. 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Like hypoxia-inducible hyper-vascularization, loss of the retinoblastoma protein (Rb) is a trait common to advanced stages of tumor progression in many metastatic cancers. However, no link between the role of Rb and hypoxia-driven metastatic processes has been established. We demonstrated that Rb is a key mediator of the hypoxic response mediated by HIF1[alpha]/[beta], the master regulator of the hypoxia response, and its essential co-activator, the thyroid hormone receptor/retinoblastoma-interacting protein (TRIP230). Furthermore, loss of Rb unmasks the full co-activation potential of TRIP230. Using small inhibitory RNA approaches in vivo, we established that Rb attenuates the normal physiological response to hypoxia by HIF1[alpha]. Notably, loss of Rb results in hypoxia-dependent biochemical changes that promote acquisition of an invasive phenotype in MCF7 breast cancer cells. In addition, Rb is present in HIF1[alpha]-ARNT/HIF1[beta] transcriptional complexes associated with TRIP230 as determined by co-immuno-precipitation, GST-pull-down and ChIP assays. These results demonstrate that Rb is a negative modulator of hypoxia-regulated transcription by virtue of its direct effects on the HIF1 complex. This work represents the first link between the functional ablation of Rb in tumor cells and HIF1[alpha]-dependent transcriptional activation and invasion.</abstract><pub>Public Library of Science</pub><doi>10.1371/journal.pone.0099214</doi></addata></record> |
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subjects | Cancer Physiological aspects Precipitation (Meteorology) Retinoblastoma RNA Transcription (Genetics) |
title | A TRIP230-Retinoblastoma Protein Complex Regulates Hypoxia-Inducible Factor-1[alpha]-Mediated Transcription and Cancer Cell Invasion |
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