Functional interaction of nuclear receptor coactivator 4 with aryl hydrocarbon receptor.
Aryl hydrocarbon receptor (AhR) transcriptional activity is enhanced by interaction with p160 coactivators. We demonstrate here that NcoA4, a nuclear receptor coactivator, interacts with and amplifies AhR action. NcoA4-AhR and NcoA4-ARNT interactions were demonstrated by immunoprecipitation in T47D breast cancer and COS cells and was independent of ligand. Overexpression of NcoA4 enhanced AhR transcriptional activity 3.2-fold in the presence of dioxin, whereas overexpression of a splice variant, NcoA4beta, as well as a variant lacking the C-terminal region enhanced AhR transcriptional activity by only 1.6-fold. Enhanced AhR signaling by NcoA4 was independent of the LXXLL and FXXLF motifs or of the activation domain. NcoA4 protein localized to cytoplasm in the absence of dioxin and in both the cytoplasm and nucleus following dioxin treatment. NcoA4-facilitation of AhR activity was abolished by overexpression of androgen receptor, suggesting a potential competition of AhR and androgen receptor for NcoA4. These findings thus demonstrate a functional interaction between NcoA4 and AhR that may alter AhR activity to affect disease development and progression.
Kollara
Alexandra
A
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ont., Canada.
Brown
Theodore J
TJ
D020816:Amino Acid Motifs; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins / Q000096:biosynthesis*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011485:Protein Binding; D020033:Protein Isoforms / Q000096:biosynthesis; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis*; D015533:Transcriptional Activation
C497396:ARNT protein, human; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D015513:Oncogene Proteins; D000072317:Polychlorinated Dibenzodioxins; D020033:Protein Isoforms; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator