Regulation of the PI3K/Akt pathway during decidualization of endometrial stromal cells

Fabi, François; Grenier, Kathy; Parent, Stefan; Adam, Pascal; Tardif, Laurence; Leblanc, Valérie; Asselin, Éric

doi:10.1371/journal.pone.0177387

Cited by 59 publications

(41 citation statements)

References 47 publications

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“…The underlying mechanism and factors responsible for the decrease of p-S473 AKT during decidualization in ESCs remains unknown. The decrease in AKT activity in decidualization is isoform specific and site specific and does not involve ubiquitin-proteasome degradation (Fabi et al 2017). Progesterone, which regulates the activation of AKT in many cell types and induces the decidualization of ESCs, may be involved.…”

Section: Figurementioning

confidence: 97%

FKBP51 regulates decidualization through Ser473 dephosphorylation of AKT

Wei¹,

Gao²,

Lu³

et al. 2018

Reproduction

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Defective decidualization of human endometrial stromal cells (ESCs) has recently been highlighted as an underlying cause of implantation failure. FK-506-binding protein 51 (FKBP51) has been shown to participate in the steroid hormone response and the protein kinase B (AKT) regulation process, both of which are important pathways involved in decidualization. The objective of the present study was to investigate the potential effects and mechanisms of FKBP51 in the regulation of ESC decidualization. By performing immunohistochemical staining on an endometrial tissue microarray (TMA) derived from normal females, we found that FKBP51 expression was much higher in the luteal phase than in the follicular phase in ESCs. Primary ESCs were isolated from patients to build an decidualization model through co-culture with medroxyprogesterone acetate (MPA) and 8-bromoadenosine (cAMP). SC79, a specific AKT activator in various physiological and pathological conditions, and shRNA-FKBP51 were used to examine the roles of AKT and FKBP51 in decidualization. The Western blot and RT-PCR results showed that FKBP51, insulin-like growth factor-binding protein 1 (IGFBP1) and prolactin (PRL) expression increased in ESCs treated with MPA + cAMP; meanwhile, the level of p-Ser473 AKT (p-S473 AKT) decreased and forkhead box protein O1 (FOXO1A) expression increased. Decidualization was inhibited by the AKT activator SC79 and the transfection of FKBP51-shRNA by affecting protein synthesis, cell morphology, cell growth and cell cycle. Furthermore, this inhibition was rescued by FKBP51-cDNA transfection. The results supported that FKBP51 promotes decidualization by reducing the Ser473 phosphorylation levels in AKT.

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Section: Figurementioning

confidence: 97%

FKBP51 regulates decidualization through Ser473 dephosphorylation of AKT

Wei¹,

Gao²,

Lu³

et al. 2018

Reproduction

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“…Indeed, the pathway resembles an interchange subway station serving additionally the decidualization and the implantation routes. One of the important functions of the pathway is to successfully inhibit Akt signaling during decidualization [ 40 ]. Indeed, recent studies on infertile women have reported that impaired Akt signaling during proliferation might contribute to endometrial ineptitude to promote relevant cascades en route to decidualization [ 41 ].…”

Section: Proliferation Route: Building the Functionalismentioning

confidence: 99%

“…Conversely, the other cAMP-induced factor, FOXO1, suppresses cyclin B1/2 and CDK1 [ 76 ]. Considering that the cAMP/PKA pathway is an inhibitor of the PI3K/Akt proliferative pathway, the complexity of cell cycle regulation during decidualization is highlighted [ 40 ]. An important role of cAMP in sensitizing endometrial cells to P4 is to prevent sumoylation of the PR by altering the expression of numerous small ubiquitin-like modifier (SUMO) enzymes [ 77 ].…”

Section: Decidualization Route: Priming the Endometrium For Implanmentioning

confidence: 99%

Inside the Endometrial Cell Signaling Subway: Mind the Gap(s)

Makieva

Giacomini

Ottolina

et al. 2018

IJMS

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Endometrial cells perceive and respond to their microenvironment forming the basis of endometrial homeostasis. Errors in endometrial cell signaling are responsible for a wide spectrum of endometrial pathologies ranging from infertility to cancer. Intensive research over the years has been decoding the sophisticated molecular means by which endometrial cells communicate to each other and with the embryo. The objective of this review is to provide the scientific community with the first overview of key endometrial cell signaling pathways operating throughout the menstrual cycle. On this basis, a comprehensive and critical assessment of the literature was performed to provide the tools for the authorship of this narrative review summarizing the pivotal components and signaling cascades operating during seven endometrial cell fate “routes”: proliferation, decidualization, implantation, migration, breakdown, regeneration, and angiogenesis. Albeit schematically presented as separate transit routes in a subway network and narrated in a distinct fashion, the majority of the time these routes overlap or occur simultaneously within endometrial cells. This review facilitates identification of novel trajectories of research in endometrial cellular communication and signaling. The meticulous study of endometrial signaling pathways potentiates both the discovery of novel therapeutic targets to tackle disease and vanguard fertility approaches.

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“…For example, KEGG annotation showed that cell junctions (focal adherens, adhesive, and tight junctions) and the PI3K–Akt signaling pathway were significantly enriched. The PI3K–Akt signaling pathway is associated with stromal cell decidualization (Z. Yang et al, ). Embryo implantation involves the events of trophocyte attachment and invasion or stoma cell migration, which may rely on cell junction changes between cell and cell or cell and matrix.…”

Section: Discussionmentioning

confidence: 99%

Altered expression patterns of circular RNAs between implantation sites and interimplantation sites in early pregnant mice

Zhang

Ding

et al. 2018

Journal Cellular Physiology

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Circular RNAs (circRNAs), a class of newly discovered endogenous noncoding RNAs, have been found to play important roles in regulating gene expression and participate in several biological processes. However, their specific roles in embryo implantation remain unclear. This study aims to investigate the roles of circRNAs in embryo implantation. In the current study, we screened the expression profiles of circRNAs between implantation sites and interimplantation sites in the endometrial tissue of early pregnant mice on Day 5 using microarray assay. Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) of four dysregulated circRNAs was performed to validate the microarray results. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and circRNA–microRNA (miRNA)–messenger RNA (mRNA) negative correlation network analyses were performed. The microarray results showed 101 upregulated and 75 downregulated circRNAs (fold change [FC] ≥ 1.5 and p value < 0.05) at implantation sites compared with interimplantation sites. Four randomly selected circRNAs were successfully verified by qRT‐PCR. The GO and KEGG analyses revealed some meaningful terms. Moreover, based on circRNAs microarray data and the miRNA and mRNA high‐throughput data previously published by our groups, differently expressed circRNAs, miRNAs, and mRNAs were performed to conjoint analysis. Then circRNA–miRNA–mRNA negative correlation networks were constructed and 21 downregulated circRNAs, 14 upregulated miRNAs, and 79 downregulated mRNAs were involved in the networks. The findings of this study may provide a novel perspective on circRNAs and lay a foundation for future research into the potential roles of circRNAs in embryo implantation.

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Regulation of the PI3K/Akt pathway during decidualization of endometrial stromal cells

Cited by 59 publications

References 47 publications

FKBP51 regulates decidualization through Ser473 dephosphorylation of AKT

FKBP51 regulates decidualization through Ser473 dephosphorylation of AKT

Inside the Endometrial Cell Signaling Subway: Mind the Gap(s)

Altered expression patterns of circular RNAs between implantation sites and interimplantation sites in early pregnant mice

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