Differential Regulation of Human 3β-Hydroxysteroid Dehydrogenase Type 2 for Steroid Hormone Biosynthesis by Starvation and Cyclic Amp Stimulation: Studies in the Human Adrenal NCI-H295R Cell Model

摘要: Human steroid biosynthesis depends on a specifically regulated cascade of enzymes including 3β-hydroxysteroid dehydrogenases (HSD3Bs). Type 2 HSD3B catalyzes the conversion pregnenolone, 17α-hydroxypregnenolone and dehydroepiandrosterone to progesterone, 17α-hydroxyprogesterone androstenedione in human adrenal cortex gonads but exact regulation this enzyme is unknown. Therefore, specific downregulation HSD3B2 at adrenarche around age 6-8 years characteristic upregulation ovaries women suffering from polycystic ovary syndrome remain unexplained prompting us study NCI-H295R cells. Our studies confirm that promoter by transcription factors GATA, Nur77 SF1/LRH1 concert NBRE/Nur77 site crucial for hormonal stimulation with cAMP. In fact, these three together were able transactivate placental JEG3 cells which normally do not express HSD3B2. By contrast, epigenetic mechanisms such as methylation acetylation seem involved controlling expression. Cyclic AMP was found exert differential effects when comparing short (acute) versus long-term (chronic) stimulation. Short cAMP inhibited activity directly possibly due co-factor or substrate level posttranslational modification protein. Long attenuated inhibition increased expression through transcriptional regulation. Although PKA MAPK pathways are obvious candidates transmitting signal HSD3B2, our using MEK1/2 inhibitors revealed no downstream signaling However, both clearly regulating