Four and a half LIM domain 2 alters the impact of aryl hydrocarbon receptor on androgen receptor transcriptional activity.
Aryl hydrocarbon receptor (AhR) ligands modulate androgen receptor (AR) signaling in prostate cancer cells through partially defined mechanisms. Furthermore, these facilitatory and inhibitory effects of AhR on AR signaling appear to be cell or context specific. In the present study we demonstrate that both AhR and AhR-nuclear translocator (ARNT) interact with AR. AhR but not ARNT enhanced the AR-transcriptional activity which was independent of exogenous AhR ligand treatment (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). We then tested if coactivators common to both receptors alter the facilitatory effect of AhR on AR activity. NcoA4 overexpression did not alter the AhR facilitatory effect on AR, whereas SRC1 overexpression further enhanced the effect. In contrast, FHL2 overexpression blocked the facilitatory effect of AhR. In the presence of exogenous FHL2 expression, AhR repressed AR activity, whereas at low endogenous levels of FHL2 expression, AhR overexpression enhanced AR activity. At high FHL2 expression levels, TCDD treatment decreased AR activity and this effect was reversed by AhR overexpression. These findings demonstrate that AhR modulation of AR activity is differentially altered by the level of FHL2 and AhR present in the cell.
Kollara
Alexandra
A
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Brown
Theodore J
TJ
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics; D056918:Nuclear Receptor Coactivators / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
C497396:ARNT protein, human; C105987:FHL2 protein, human; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; C111382:NCOA4 protein, human; D056918:Nuclear Receptor Coactivators; D000072317:Polychlorinated Dibenzodioxins; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D014157:Transcription Factors; D013196:Dihydrotestosterone; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004247:DNA; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D017430:Prostate-Specific Antigen