3',5'-cyclic adenosine monophosphate response element binding protein up-regulated cytochrome P450 lanosterol 14alpha-demethylase expression involved in follicle-stimulating hormone-induced mouse oocyte maturation

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2008-07, Vol.22 (7), p.1682-1694
• Main Authors: Ning, Gang, Ouyang, Hong, Wang, Songbo, Chen, Xiufen, Xu, Baoshan, Yang, Jiange, Zhang, Hua, Zhang, Meijia, Xia, Guoliang
• Format: Article
• Language: English
• Subjects: Animals; Cyclic AMP - analogs & derivatives; Cyclic AMP - metabolism; Cytochrome P-450 Enzyme System - metabolism; Female; Follicle Stimulating Hormone - metabolism; Gene Expression Regulation, Enzymologic; Ketoconazole - pharmacology; Meiosis; Mice; Models, Biological; Oocytes - cytology; Oocytes - metabolism; Receptors, Androgen - metabolism; Response Elements; Sterol 14-Demethylase; Up-Regulation
• ISSN: 0888-8809
• DOI: 10.1210/me.2007-0480

Cytochrome P450 lanosterol 14alpha-demethylase (CYP51) is a key enzyme in sterols and steroids biosynthesis that can induce meiotic resumption in mouse oocytes. The present study investigated the expression mechanism and function of CYP51 during FSH-induced mouse cumulus oocyte complexes (COCs) meiotic resumption. FSH increased cAMP-dependent protein kinase (PKA) RIIbeta level and induced cAMP response element-binding protein (CREB) phosphorylation and CYP51 expression in cumulus cells before oocyte meiotic resumption. Moreover, CYP51 and epidermal growth factor (EGF)-like factor [amphiregulin (AR)] expression were blocked by (2)-naphthol-AS-Ephosphate (KG-501) (a drug interrupting the formation of CREB functional complex). KG-501 and RS21607 (a specific inhibitor of CYP51 activity) inhibited oocyte meiotic resumption, which can be partially rescued by progesterone. These two inhibitors also inhibited FSH-induced MAPK phosphorylation. EGF could rescue the suppression by KG-501 but not RS21607. Furthermore, type II PKA analog pairs, N(6)-monobutyryl-cAMP plus 8-bromo-cAMP, increased PKA RIIbeta level and mimicked the action of FSH, including CREB phosphorylation, AR and CYP51 expression, MAPK activation, and oocyte maturation. All these data suggest that CYP51 plays a critical role in FSH-induced meiotic resumption of mouse oocytes. CYP51 and AR gene expression in cumulus cells are triggered by FSH via a type II PKA/CREB-dependent signal pathway. Our study also implicates that CYP51 activity in cumulus cells participates in EGF receptor signaling-regulated oocyte meiotic resumption.