RGS2 promotes estradiol biosynthesis by trophoblasts during human pregnancy

Abstract

Production of estradiol (E2) by the placenta during human pregnancy ensures successful maintenance of placental development and fetal growth by stimulating trophoblast proliferation and the differentiation of cytotrophoblasts into syncytiotrophoblasts. Decreased levels of E2 are closely associated with obstetrical diseases such as preeclampsia (PE) in the clinic. However, the mechanisms underlying the inhibition of placental E2 biosynthesis remain poorly understood. Here, we report that regulator of G-protein signaling 2 (RGS2) affects E2 levels by regulating aromatase, a rate-limiting enzyme for E2 biosynthesis, by using human trophoblast-derived JEG-3 cells and human placental villus tissues. RGS2 enhanced the protein degradation of the transcription factor heart and neural crest derivatives expressed 1 (HAND1) by suppressing ubiquitin-specific protease 14 (USP14)-mediated deubiquitination of HAND1, resulting in the restoration of HAND1-induced trans-inactivation of the aromatase gene and subsequent increases in E2 levels. However, aromatase bound to RGS2 and repressed RGS2 GTPase activating protein (GAP) activity. Moreover, we observed a positive correlation between RGS2 and aromatase expression in clinical normal and preeclamptic placental tissues. Our results uncover a hitherto uncharacterized role of the RGS2-aromatase axis in the regulation of E2 production by human placental trophoblasts, which may pinpoint the molecular pathogenesis and highlight potential biomarkers for related obstetrical diseases.

ARID1A restrains EMT and stemness of ovarian cancer cells through the Hippo pathway

“…ShRNA sequences used are as follows: shRNA sequence targeting ARID1A: 5'-AAC CAA AGT TAC TGT TGT TTA-3'; and a scrambled shRNA sequence (5'-TTT GTA CTA CAC AAA AGT ACTG-3') was used as control. Sequences were obtained from Shanghai Sangon Biotechnology Co. Ltd. Lentiviruses expressing ARID1A-shRNA or scrambled-shRNA were generated by co-transfecting the HEK293T packaging cells with lentiviral shRNA expression vector, and lentiviruses-containing supernatants with the titers greater than 1×10 6 cfu/ml was used for infection of cells in the presence of 8 μ g/ml polybrene (Sigma-Aldrich; Merck KGaA) as previously described ( 21 ).…”

“…Total RNA was extracted from SK-OV-3 cells and A2780 cells by using a TRIzol reagent (Takara Biotechnology Co., Ltd.) according to the manufacturer's instructions. 5 μ g of total RNA was reversely transcribed by using SuperScript III reagent (Thermo Fisher Scientific, Inc.) according to the manufacturer's protocol, and the oligo-(deoxythymidine) primer with incubation at 42°C for 1 h. After the termination of cDNA synthesis, mRNA levels of target genes were determined by RT-qPCR as previously described ( 21 ). Briefly, the initial denaturation was 95°C for 5 min; followed by 40 cycles of denaturation (95°C, 10 sec), annealing and extension (60°C, 30 sec).…”

Basic Research Advances in China on Embryo Implantation, Placentation, and Parturition

“…Specifically, RGS2 promoted protein degradation of HAND1 and restored transcription of HAND1-inhibited aromatase, leading to increased estrogen levels. 73 In addition to the abovementioned hormones, Yu et al 74 identified placensin, a peptide hormone derived from the placenta, which is capable of stimulating glucose secretion and trophoblast invasion. Serum placensin level rises in a stage-dependent manner during pregnancy and is significantly increased in patients with gestational diabetes mellitus during the third trimester.…”

“…A recent study showed an uncharacterized role of RGS2 in the production of estrogen by the placenta. Specifically, RGS2 promoted protein degradation of HAND1 and restored transcription of HAND1-inhibited aromatase, leading to increased estrogen levels 73 . In addition to the abovementioned hormones, Yu et al 74 .…”