17β-Estradiol-Induced Regulation of the Novel 5-HT1A-Related Transcription Factors NUDR and Freud-1 in SH SY5Y Cells

Nuclear deformed epidermal autoregulatory factor-1 (NUDR/Deaf-1) and five prime repressor element under dual repression (Freud-1) are novel transcriptional regulators of the 5-HT1A receptor, a receptor that has been implicated in the pathophysiology of various psychiatric illnesses. The antidepressant effect of 17 beta-Estradiol (17 beta E-2) is purported to involve the downregulation of this receptor. We investigated the possible role of NUDR and Freud-1 in 17 beta E-2-induced downregulation of the 5-HT1A receptor in the neuroblastoma cell line SH SY5Y. Cells were treated with 10 nM of 17 beta E-2 for 3 or 48 h, followed by a 24-h withdrawal period. Proteins were isolated and analyzed by western blotting. 17 beta E-2 treatment increased NUDR immunoreactivity while Freud-1 and the 5-HT1A receptor showed significant decreases. Upon withdrawal of 17 beta E-2, protein expression returned to control levels, except for NUDR, which remained significantly elevated in the 3-h treatment. Taken together, these data support a non-genomic downregulation of 5-HT1A receptor protein by 17 beta E-2, which does not involve NUDR and Freud-1. Rather, changes in both transcription factors seem to be compensatory/homeostatic responses to changes in 5-HT1A receptor induced by 17 beta E-2. These observations further highlight the importance of NUDR and Freud-1 in regulating 5-HT1A receptor expression.