The ovarian follicle develops as a functional unit which comprises of theca cells, granulosal cells, and oocyte. The theca cells are the primary source to synthesize androgen in response to LH [
1‐
3]. Besides, the synthesis of androgen in theca cells is also regulated by a variety of additional steroidogenic enzymes. It is well known that theca cells express cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase (HSD3B2), and cytochrome P450 cytochrome P450 17α-hydroxylase (CYP17A1) which has both 17α-hydroxylase and C17, 20 lyase activities [
4]. All of these are key enzymes for androgen synthesis. In addition, steroidogenic acute regulatory (StAR) protein which facilitates cholesterol entry into the mitochondria mediates the rate-limiting step in the synthesis of androgen [
5]. The regulation of these enzymes plays a critical role in normal androgen production and plays a proposed role in the pathogenic hyperandrogenic conditions such as Polycystic Ovarian Syndrome (PCOS) [
6,
7].
The SET protein (patient “SE translocation”), also known as TAF-1β [
8], I2PP2A [
9] and INHAT [
10], belongs to a family of multitasking proteins, which is involved in apoptosis, transcription, nucleosome assembly, and histone binding.
SET is located in chromesome 9q34 and encodes a 39 KDa phosphoprotein. It was originally identified as a translocated gene in acute undifferentiated leukemia [
11]. In addition, as a transcriptional regulating factor, SET not only exerts by binding to the transcriptional co-activators CBP/p300 [
12], but also acts directly as a transcriptional factor of CYP17A1 [
13]. SET-mediated promoter hypoacetylation is a prerequisite for co-activation of the estrogen-responsive pS2 gene by PRMT1 [
14]. SET is widely expressed in various tissues, especially in steroidogenic cells within the central nervous system, adrenal glands, and gonads [
13,
15,
16]. In rat ovaries, SET protein expressed in theca cells and oocytes [
15]. In human ovaries we found that SET protein also expressed predominantly in theca cells and oocytes (unpublished data). Recent evidence suggested that SET was essential for regulating both the promoter activity of CYP17A1 and the biological activity of P450c17. In human NT2 neuronal precursor cells and MA-10 cells, SET binds to rat CYP17A1 promoter at −418/-399 and activates its basal transcription from a rat CYP17A1 luciferase reporter plasmid [
13,
15,
17]. In addition, SET has been identified as a potent inhibitor of the protein phosphatase 2A (PP2A). Miller et al. showed that, in NCI-H295A cells, SET can foster 17, 20 lyase activity of P450c17 by inhibiting the dephosphorylation action of PP2A on P450c17 [
18], because the phosphorylation of P450c17 on serine and threonine residues increases its17, 20 lyase activity through as-yet-unidentified mechanisms, which may involve in increasing its affinity for
b5 and/or P450 oxidoreductase [
19].
Although the function of SET protein in some steroidogenic cells such as adrenal glands cells has been partly studied, the role of SET in androgen biosynthesis of ovarian theca cells has not been explored previously. Our previous studies have also found that SET was one of the overexpressed genes in polycystic ovaries compared to normal ovaries using cDNA microarray technology [
20]. All of these attracted us to explore the function of SET in the regulation of ovarian androgen biosynthesis. This study may also help us to understand the pathophysiological role of SET in hyperandrogenism of PCOS.