Prolyl oligopeptidase regulates progesterone secretion via the ERK signaling pathway in murine luteal cells

• Published in: Molecular reproduction and development 2019-06, Vol.86 (6), p.714-726
• Main Authors: Xu, Ping, Bao, Riqiang, Zhang, Yaqiong, Lu, Enhang, Feng, Fen, Zhang, Luyin, Li, Jiaheng, Wang, Jing, Tan, Ximin, Tang, Min, Hu, Chuan, Li, Gang, Zhang, Chunping
• Format: Article
• Language: English
• Subjects: Animals; Cholesterol; Cholesterol Side-Chain Cleavage Enzyme - metabolism; Corpus luteum; Enzymes; ERK signaling pathway; Extracellular signal-regulated kinase; Female; Kinases; luteal cells; Luteal Cells - cytology; Luteal Cells - enzymology; MAP Kinase Signaling System - physiology; Mice; Oligopeptidase; Ovaries; Phosphoproteins - metabolism; Phosphorylation; POP; Progesterone; Progesterone - metabolism; Prolyl oligopeptidase; RNA Splicing Factors - metabolism; Secretion; Serine; Serine Endopeptidases - metabolism; SF1; Signal transduction; Steroid 11-beta-Hydroxylase - metabolism; Steroidogenic acute regulatory protein; Steroidogenic factor 1
• ISSN: 1040-452X; 1098-2795
• DOI: 10.1002/mrd.23149

Prolyl oligopeptidase (POP), one of the most widely distributed serine endopeptidases, is highly expressed in the ovaries. However, the physiological role of POP in the ovaries is not clear. In this study, we investigated the significance of POP in the corpus luteum. Murine luteal cells were cultured in vitro and treated with a POP selective inhibitor, (2S)‐1[[(2 S)‐1‐(1‐oxo‐4‐phenylbutyl)‐2‐pyrrolidinyl carbonyl]‐2‐pyrrolidinecarbonitrile (KYP‐2047). We found that KYP‐2047 treatment decreased progesterone secretion. In contrast, POP overexpression increased progesterone secretion. Three essential steroidogenic enzymes, including p450 cholesterol side‐chain cleavage enzyme (CYP11A), 3β‐hydroxysteroid dehydrogenase (3β‐HSD), and the steroidogenic acute regulatory protein (StAR), were regulated by POP. Further studies showed that POP overexpression increased ERK1/2 phosphorylation and increased the expression of steroidogenic factor 1 (SF1), while KYP‐2047 treatment decreased ERK1/2 phosphorylation and SF1 expression. To clarify the role of ERK1/2 signaling in POP‐regulated progesterone synthesis, U0126‐EtOH, an inhibitor of the ERK signaling pathway, was used to treat luteal cells. We found that U0126‐EtOH decreased progesterone production and the expression of steroidogenic enzymes and SF1. POP overexpression did not reverse the effects of U0126‐EtOH. Overall, POP regulates progesterone secretion by stimulating the expression of CYP11A, 3β‐HSD, and StAR in luteal cells. ERK signaling and downstream SF1 expression contribute to this process. Prolyl oligopeptidase (POP) regulates the progesterone secretion in luteal cells through a cascade of the event, including ERK signaling, downstream SF‐1, and steroidogenic genes (Cyp11a1, Hsd3b, and Star) (Figure 8). This study improved our understanding of POP biological function in the corpus luteum.