Abstract
CYP11A1 is a key enzyme in steroid hormone synthesis which is regulated by steroidogenic factor-1 (SF-1). In order to investigate the regulation and functions of Cyp11a1, I used the cell culture system and mice which were mutated on the SF-1 response element (SF1RE) of Cyp11a1 promoter for further studying. In this study, I demonstrated the mutated proximal SF1RE on Cyp11a1 promoter regulated its transcriptional activity cell type specifically. In Cyp11a1L/L mice, this mutation results in the decrease of CYP11A1 expression in the adrenal and testis, but the expression in the ovary was normal. Even though CYP11A1 expression level is reduced to 15% of the normal amount, the life span, fertility, steroid levels, and behavior of Cyp11a1L/L mice were similar as that of wildtype mice at the resting state. The reduction of CYP11A1 attenuated the circadian rhythm of corticosterone levels. These mice also failed to secrete more glucocorticoid in response to stress, leading to inability to inhibit the production of stress-induced inflammatory cytokines and increased mortality. In addition, mutant mice also showed defects in maintaining energy homeostasis when fasting. Thus, CYP11A1 appears in normal mice to be expressed above the minimal required level, providing a large reserve capacity for use in response to stress. Mutation of the SF1RE of Cyp11a1 results in reduced stress response due to decreased CYP11A1 expression and insufficient stress-induced glucocorticoids secretion.