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21 August 2013 The ERK1/2 Signaling Pathway Regulates 11beta-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells Through a Transcriptional Mechanism
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Abstract

The placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2; encoded by the HSD11B2 gene) plays a key role in fetal development, but its regulation is incompletely understood. We previously demonstrated that p38 MAPK was a positive regulator of placental 11beta-HSD2. However, it remains unknown if the other two MAPKs, ERK1/2 and JNK, were also involved. In the present study, we identified ERK1/2 as an important regulator of placental 11beta-HSD2. We showed that inhibition of ERK1/2 with the pharmacological inhibitor U0126 led to a 3-fold increase in 11beta-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. In contrast, the JNK inhibitor SP600125 had no effect. Furthermore, U0126 increased the HSD11B2 promoter activity by 300%, indicating that ERK1/2 regulates placental 11beta-HSD2 expression through a transcriptional mechanism. Importantly, siRNA-mediated knockdown of ERK1/2 caused a similar increase in 11beta-HSD2 protein. In addition, given that we previously showed that cadmium reduced placental 11beta-HSD2 expression via a transcriptional mechanism, but the signal transduction pathways involved remain unclear, we also addressed this question and found that treatment of trophoblast cells with cadmium led to rapid activation of ERK1/2. Importantly, U0126 completely abrogated the inhibitory effects of cadmium on placental 11beta-HSD2. Taken together, the present study not only identifies the ERK1/2 signaling pathway as a potent negative regulator of placental 11beta-HSD2 but also demonstrates that this pathway mediates cadmium repression of placental 11beta-HSD2. Thus, our present study reveals 11beta-HSD2 as an important target through which ERK1/2 may regulate human placental function and consequently fetal development.

Haiyan Guan, Kang Sun, and Kaiping Yang "The ERK1/2 Signaling Pathway Regulates 11beta-Hydroxysteroid Dehydrogenase Type 2 Expression in Human Trophoblast Cells Through a Transcriptional Mechanism," Biology of Reproduction 89(4), (21 August 2013). https://doi.org/10.1095/biolreprod.113.110924
Received: 20 May 2013; Accepted: 1 August 2013; Published: 21 August 2013
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