Differential regulation of mTORC1 and mTORC2 is critical for 8-Br-cAMP-induced decidualization

Baek, Mi Ock; Song, Hae In; Han, Joong‐Soo; Yoon, Mee Sup

doi:10.1038/s12276-018-0165-3

Cited by 20 publications

(14 citation statements)

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“…Decidualization of the human endometrium involves a notable morphological and functional differentiation of human endometrial stromal cells, which is a crucial step in making a uterus receptive to an embryo [33]. cAMP-mediated protein kinase A (PKA) activation is critical for the initiation of decidualization and decidual PRL and IGFBP1 are major secretory products of the decidualized endometrium [34]. We showed that EHD1 expression gradually decreased in response to 8-Br-cAMP and MPA treatment in a time-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure

et al. 2019

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a b s t r a c tBackground: Recurrent implantation failure (RIF) remains a critical and challenging problem in assisted reproductive technology mainly due to impaired decidualization. The endocytic and transcytotic activity in the endometrium are crucial for decidualization. The most representative endocytic gene is the Cterminal Eps15 homology domain-containing 1 (EHD1), but whether EHD1-mediated endocytic function is responsible for embryo implantation during decidualization remains unclear. Methods: A transcriptomic analysis was performed to evaluate the differentially expressed genes between the fertile control and RIF group. The expression and location of EHD1 in endometrial tissues were further examined by IHC, qRT-PCR and Western blotting. The transduction of an EHD1 recombinant adenovirus into human endometrial stromal cells was performed to investigate relevant decidualization marker genes. Additionally, a microarray analysis following the adenovirus-mediated overexpression of EHD1 was conducted to identify EHD1-related changes in HESCs, and the potential molecular mechanisms were further confirmed through immunofluorescence and coimmunoprecipitation analyses. Findings: An RNA-seq analysis demonstrated that EHD1 expression was significantly higher in the midsecretory endometrium of the RIF group than in that of the fertile control group. The analysis of the menstrual cycle showed that expression of EHD1 increased in the mid-proliferative phase and showed a gradual decrease in the mid-secretory and decidual phases. Furthermore, EHD1 overexpression impaired decidualization by suppressing the expression of prolactin and insulin-like growth factor binding protein-1 and the formation of the cytoskeleton. The mechanistic analysis revealed the EHD1 regulated LRP5/6 protein function through the endocytic pathway, and subsequently suppressed the Wnt4/ β-catenin pathway during decidualization. In addition, a Wnt4 agonist improved an impaired decidualization process. Interpretation: Regulation of the EHD1-Wnt4 pathway might serve as a promising therapeutic strategy for improving endometrial receptivity in RIF women.Recurrent implantation failure (RIF) remains a critical and challenging problem in assisted reproductive technology mainly because of impaired decidualization. Endocytic and transcytotic activity in the endometrium are crucial for impaired decidualization. The most representative endocytic genes is the C-terminal Eps15 homology domain-containing 1 (EHD1). Whether the EHD1https://doi.

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Section: Resultsmentioning

confidence: 99%

EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure

et al. 2019

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“…However, SM exposure-induced FOXO3a deletion was sufficient to inhibit the expression of autophagic genes and subsequent autophagic flux in undifferentiated eSCs. It is possible that FOXO3a is the main member of the FOXO family that maintains autophagy in undifferentiated eSCs, since FOXO3a is highly expressed in those cells, while FOXO1 is expressed in the decidualized endometrium in vitro 36 and in vivo 34 , and FOXO4 is not expressed in the normal endometrium 34 . The role of autophagy in migration has been recently demonstrated 37 .…”

Section: Discussionmentioning

confidence: 99%

“…For immunoprecipitation, lysis buffer containing 40 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (pH 7.4), 120 mM NaCl, 10 mM pyrophosphate, 50 mM NaF, 10 mM β-glycerophosphate, 2 mM EDTA, 1X Sigma protease inhibitor cocktail, and 0.3% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate was used. Western blotting was performed as previously described 36 .…”

Section: Methodsmentioning

confidence: 99%

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Microgravity inhibits decidualization via decreasing Akt activity and FOXO3a expression in human endometrial stromal cells

Cho

Baek

Khaliq

et al. 2019

Sci Rep

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Decidualization is characterized by the differentiation of endometrial stromal cells (eSCs), which is critical for embryo implantation and maintenance of pregnancy. In the present study, we investigated the possible effect of simulated microgravity (SM) on the process of proliferation and in vitro decidualization using primary human eSCs. Exposure to SM for 36 h decreased the proliferation and migration of eSCs significantly, without inducing cell death and changes in cell cycle progression. The phosphorylation of Akt decreased under SM conditions in human eSCs, accompanied by a simultaneous decrease in the level of matrix metalloproteinase (MMP)-2 and FOXO3a. Treatment with Akti, an Akt inhibitor, decreased MMP-2 expression, but not FOXO3a expression. The decreased level of FOXO3a under SM conditions impeded autophagic flux by reducing the levels of autophagy-related genes. In addition, pre-exposure of eSCs to SM significantly inhibited 8-Br-cAMP induced decidualization, whereas restoration of the growth status under SM conditions by removing 8-Br-cAMP remained unchanged. Treatment of human eSCs with SC-79, an Akt activator, restored the reduced migration of eSCs and decidualization under SM conditions. In conclusion, exposure to SM inhibited decidualization in eSCs by decreasing proliferation and migration through Akt/MMP and FOXO3a/autophagic flux.

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“…In vitro decidualization was induced by plating the cells and growing them to 100% confluency by treating them with DMEM containing 10% FBS, 1% penicillin/streptomycin (10,000 U/mL), and 0.5 mM 8-bromo adenosine 3 5 -cyclic adenosine monophosphate (8-Br-cAMP). Fresh medium was provided on alternate days (Baek et al, 2018).…”

Section: Isolation and Culture Of Human Escsmentioning

confidence: 99%

C-Peptide Inhibits Decidualization in Human Endometrial Stromal Cells via GSK3β-PP1

Khaliq

Baek

Cho

et al. 2020

Front. Cell Dev. Biol.

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Decidualization refers to the functional differentiation of endometrial stromal cells and plays a significant role in embryo implantation and pregnancy. C-peptide is excreted in equimolar concentrations as that of insulin during the metabolism of proinsulin in pancreatic beta-cells. High levels of C-peptide are correlated with hyperinsulinemia and polycystic ovarian syndrome, which show a defect in decidualization. However, the role of C-peptide in decidualization has not yet been studied. Here, we identified C-peptide as an endogenous antideciduogenic factor. This inhibitory function was confirmed by the reduced expression of decidual markers, including prolactin, insulin-like growth factor-binding protein-1, and Forkhead box protein O1 as well as by the fibroblastic morphological change in the presence of C-peptide. C-peptide also enhanced cellular senescence and decreased the proportion of apoptotic cells during decidualization. In addition, C-peptide potentiated the inhibitory effects of both insulin and palmitic acid in an AKT- and autophagy-independent manner, respectively. Furthermore, C-peptide augmented protein phosphatase 1 (PP1) activity, leading to a reduction in the inhibitory phosphorylation of glycogen synthase kinase (GSK)3β, which resulted in enhanced cellular senescence and decreased apoptosis during decidualization. Taken together, our findings suggest that C-peptide is an antideciduogenic factor acting via the regulation between PP1 and GSK3β in patients with hyperinsulinemia.

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Differential regulation of mTORC1 and mTORC2 is critical for 8-Br-cAMP-induced decidualization

Cited by 20 publications

References 62 publications

EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure

EHD1 impairs decidualization by regulating the Wnt4/β-catenin signaling pathway in recurrent implantation failure

Microgravity inhibits decidualization via decreasing Akt activity and FOXO3a expression in human endometrial stromal cells

C-Peptide Inhibits Decidualization in Human Endometrial Stromal Cells via GSK3β-PP1

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