Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially.
Previous studies from our group have shown that Foxa1 is expressed in the prostate and interacts with the androgen receptor (AR) to regulate prostate-specific genes such as prostate-specific antigen (PSA) and probasin (PB). We report here that Foxa2 but not Foxa1 is expressed in the epididymis. Further, Foxa2 interacts with the AR to regulate the mouse epididymal retinoic acid binding protein (mE-RABP) gene, an epididymis-specific gene. Binding of Foxa2 to the mE-RABP promoter was confirmed by gel-shift and chromatin immunoprecipitation (ChIP) assays. Overexpression of Foxa2 suppresses androgen activation of the mE-RABP promoter while overexpression of Foxa2 with prostate-specific promoters activates gene expression in an androgen-independent manner. GST pull-down assays determined that both Foxa1 and Foxa2 physically interact with the DNA binding domain of the AR. The interaction between Foxa proteins and AR was further confirmed by gel-shift assays where Foxa protein was recruited to AR binding oligomers even when Foxa binding sites were not present, and AR was recruited to Foxa binding oligomers even in the absence of an AR binding site. Given that Foxa1 and Foxa2 proteins are expressed differentially in the prostate and epididymis, these data suggest that the Foxa proteins have distinct effects on AR-regulated genes in different male reproductive accessory organs.
Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Xiuping
X
Yu
Aparna
A
Gupta
Yongqing
Y
Wang
Kichiya
K
Suzuki
Janni
J
Mirosevich
Marie-Claire
MC
Orgebin-Crist
Robert J
RJ
Matusik
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004822:Epididymis / Q000378:metabolism*; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma; D014162:Transfection
D000728:Androgens; C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; C112597:Lcn5 protein, mouse; D011944:Receptors, Androgen; D018168:Receptors, Retinoic Acid; D054839:Retinol-Binding Proteins, Plasma; D051542:Hepatocyte Nuclear Factor 3-beta