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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Bibliographic Details
Published in:PloS one 2014-06, Vol.9 (6)
Main Authors: 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
Format: Article
Language:English
Subjects:
Cancer
Physiological aspects
Precipitation (Meteorology)
Retinoblastoma
RNA
Transcription (Genetics)
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0099214