Herbicide atrazine activates SF-1 by direct affinity and concomitant co-activators recruitments to induce aromatase expression via promoter II.
The popular herbicide atrazine is an endocrine disruptor that demasculinizes and feminizes several species of animals, and co-relates with breast and reproductive disorders in mammalians. We recently reported that atrazine induces human aromatase gene expression via promoter II (ArPII) in a steroidogenic factor 1 (SF-1)-dependent manner. Here, we show that knockdown of SF-1 abolishes ArPII induction by atrazine in H295R cells, which harbor high SF-1 expression and are originally atrazine-responsive. Conversely, exogenous SF-1 enables atrazine to induce ArPII in the otherwise non-responsive KGN cells. Atrazine's effect is independent from protein kinase A and LRH-1, a close relative of SF-1. However, it binds directly to the SF-1, and concomitantly, enhances interactions of SF-1 with co-activator TIF2, and renders more SF-1 binding to ArPII chromatin. Intriguingly, LBD mutations do not alter SF-1's ability to mediate atrazine stimulation, suggesting that atrazine interacts with SF-1 via a region(s) other than the ligand binding pocket. These data suggest that atrazine binds to and activates SF-1 to induce ArPII.
Fan
Wuqiang
W
Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Yanase
Toshihiko
T
Morinaga
Hidetaka
H
Gondo
Shigeki
S
Okabe
Taijiro
T
Nomura
Masatoshi
M
Hayes
Tyrone B
TB
Takayanagi
Ryoichi
R
Nawata
Hajime
H
D000818:Animals; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism*; D001280:Atrazine / Q000494:pharmacology*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006540:Herbicides / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D006540:Herbicides; D018398:Homeodomain Proteins; C515057:NR5A1 protein, human; C082631:NR5A2 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D001141:Aromatase; D017868:Cyclic AMP-Dependent Protein Kinases; D001280:Atrazine