Recruitment of thyroid hormone receptor/retinoblastoma-interacting protein 230 by the aryl hydrocarbon receptor nuclear translocator is required for the transcriptional response to both dioxin and hypoxia.
The aryl hydrocarbon receptor nuclear translocator/hypoxia-inducible factor (ARNT/HIF-1 beta) mediates an organism's response to various environmental cues, including those to chemical carcinogens, such as 2,3,7,8-tetrachlorodibenzo-rho-dioxin (TCDD or dioxin), via its formation of a functional transcription factor with the ligand activated aryl hydrocarbon receptor (AHR). Similarly, tissue responses to hypoxia are largely mediated through the HIF-1 heterodimeric transcription factor, comprising hypoxia-inducible factor-1 alpha (HIF-1 alpha) and ARNT. The latter response is essential for a metabolic switch from oxidative phosphorylation to glycolytic anaerobic metabolism as well as for angiogenesis and has been implicated as necessary for growth in many solid tumors. In this report, we demonstrate that the thyroid hormone receptor/retinoblastoma-interacting protein 230 (TRIP230) interacts directly with ARNT and is essential for both hypoxic and TCDD-mediated transcriptional responses. We initially identified TRIP230 as an ARNT-interacting protein in a yeast two-hybrid assay screen. This interaction was confirmed in mammalian cell systems using co-immunoprecipitation and in mammalian two-hybrid assays. Furthermore, TRIP230 could be recorded at sites of activated transcription of either TCDD- or hypoxia-inducible genes in a stimulus-dependent fashion by chromatin immunoprecipitation analysis. Finally, using single-cell microinjection and RNA interference assays, we demonstrate that TRIP230 is indispensable for TCDD- and hypoxia-dependent gene transcription.
Department of Pathology and Laboratory Medicine, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Timothy V
TV
Beischlag
Robert T
RT
Taylor
David W
DW
Rose
Diana
D
Yoon
Yumay
Y
Chen
Wen-Hwa
WH
Lee
Michael G
MG
Rosenfeld
Oliver
O
Hankinson
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004147:Dioxins / Q000494:pharmacology*; D004347:Drug Interactions; D015870:Gene Expression; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007163:Immunosorbent Techniques; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology*; D012441:Saccharomyces cerevisiae; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D020798:Two-Hybrid System Techniques
C497396:ARNT protein, human; C497397:Arnt protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D004147:Dioxins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; C109331:TRIP11 protein, human; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator