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.

Enhancement of folate receptor alpha expression in tumor cells through the glucocorticoid receptor: a promising means to improved tumor detection and targeting.

The utility of the folate receptor (FR) type alpha, in a broad range of targeted therapies and as a diagnostic serum marker in cancer, is confounded by its variable tumor expression levels. FR-alpha, its mRNA and its promoter activity were coordinately up-regulated by the glucocorticoid receptor (GR) agonist, dexamethasone. Optimal promoter activation which occurred at <50 nmol/L dexamethasone was inhibited by the GR antagonist, RU486, and was enhanced by coactivators, supporting GR mediation of the dexamethasone effect.

Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting.

The folate receptor (FR) type alpha is a promising target for diagnostic imaging agents and therapeutic intervention in major subtypes of gynecological malignancies; however, the receptor levels in the tumors are variable and are generally relatively low in estrogen receptor (ER)-positive tumors. Here we report that the FR-alpha gene promoter is repressed in the presence of 17beta-estradiol and derepressed by the antiestrogens tamoxifen and ICI 182780 in a promoter-specific and ER-alpha-dependent manner in carcinoma cell lines including HeLa (cervical carcinoma), BG-1 (ovarian carcinoma), and IGROV-1 (ovarian carcinoma). The ligand and ER dose response of the FR-alpha promoter and its time course paralleled those of a classical estrogen response element-mediated effect.

Dual regulation of ets-activated gene expression by SP1.

The human folate receptor (hFR) type gamma gene is driven by a TATA-less promoter that uses a canonical Sp1 element for basal transcription. Using nuclear extract from 293 (human embryonic) cells, we mapped a second (non-canonical) Sp1 element to which Sp1 bound with a comparable affinity and which overlaps a functional ets binding site (EBS). Mutagenesis experiments revealed that the binding of ets to the EBS activates the promoter synergistically with Sp1 bound at the downstream site; however, binding of Sp1 to the EBS does not contribute to promoter activity.