Androgen activation of the folate receptor α gene through partial tethering of the androgen receptor by C/EBPα.
The folate receptor α (FRα) is critical for normal embryonic and fetal development. The receptor has a relatively narrow tissue specificity which includes the visceral endoderm and the placenta and mediates delivery of folate, inadequacy of which results in termination of pregnancy or developmental defects. We have previously reported that the FRα gene is negatively and directly regulated by estrogen and positively but indirectly by progesterone and glucocorticoid. To further investigate hormonal control of this gene and in view of the growing evidence for the importance of the androgen receptor (AR) in endometrial and placental functions, we examined the response of the FRα gene to androgen. Here we demonstrate that the FRα gene is directly activated by androgen. The P4 promoter of the FRα gene is the target of hormone-dependent activation by the androgen receptor (AR) in a manner that is co-activator-dependent. The site of functional association of AR in the FRα gene maps to a 35bp region occurring ∼1500bp upstream of the target promoter. The functional elements within this region are an androgen response element (ARE) half-site and a non-canonical C/EBP element that cooperate to recruit AR in a manner that is dependent on the DNA-bound C/EBPα. Since the placenta is rich in C/EBPα, the findings underscore the multiplicity of mechanisms by which the FRα gene is under the exquisite control of steroid hormones.
Sivakumaran
Suneethi
S
Department of Biochemistry and Cancer Biology, Medical University of Ohio, 3000 Arlington Avenue, Toledo, OH 43614, United States.
Zhang
Juan
J
Kelley
Karen M M
KM
Gonit
Mesfin
M
Hao
Hong
H
Ratnam
Manohar
M
D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection
C410798:AR protein, human; D022763:CCAAT-Enhancer-Binding Protein-alpha; D058973:Folate Receptors, GPI-Anchored; D011944:Receptors, Androgen
BMC Dev Biol. 2007 Dec 19;7:137
18093301
Birth Defects Res A Clin Mol Teratol. 2009 Apr;85(4):303-13
19180647
J Biol Chem. 1989 Sep 5;264(25):14893-901
2768245
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D108-10
16381825
Mol Cell Biol. 2003 Mar;23(6):2202-12
12612090
Dev Cell. 2002 Apr;2(4):411-23
11970892
J Clin Endocrinol Metab. 2005 Jul;90(7):4315-21
15814773
Reprod Sci. 2009 Feb;16(2):191-9
19208787
Mol Genet Metab. 1999 Jan;66(1):31-9
9973545
Expert Rev Mol Med. 2009 Jan 28;11:e4
19173758
Nucleic Acids Res. 2003 Jul 1;31(13):3576-9
12824369
Biochem J. 1993 Aug 1;293 ( Pt 3):761-8
8352744
Am J Hum Genet. 2009 Sep;85(3):354-63
19732866
Adv Drug Deliv Rev. 2004 Apr 29;56(8):1085-97
15094208
Mol Endocrinol. 2007 Mar;21(3):635-50
17192405
Biochem J. 2002 Aug 1;365(Pt 3):561-75
12006103
Biochemistry. 1991 Jun 11;30(23):5674-81
1904273
Public Health Nutr. 2001 Apr;4(2B):601-9
11683553
Cancer Res. 2005 May 15;65(10):4431-41
15899836
Oncogene. 2010 Feb 4;29(5):723-38
19901962
Oncogene. 2007 Dec 13;26(57):7872-84
17599049
Nat Genet. 1999 Oct;23(2):228-32
10508523
Adv Drug Deliv Rev. 2004 Apr 29;56(8):1067-84
15094207
J Clin Invest. 1989 Aug;84(2):715-20
2527252
Cancer Res. 2003 Jun 1;63(11):2820-8
12782587
Blood. 1992 Jun 1;79(11):2807-20
1586732
Endocrinology. 2008 Sep;149(9):4462-74
18511503
Mol Endocrinol. 2006 May;20(5):984-95
16455820
Biochemistry. 1995 Nov 7;34(44):14594-600
7578066
J Biol Chem. 2000 Apr 21;275(16):12290-7
10766868
Biochemistry. 1989 Oct 3;28(20):8249-54
2605182