Dataset Information

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

ABSTRACT: Human endometrium decidualization, a differentiation process involving biochemical and morphological changes, is a prerequisite for embryo implantation and successful pregnancy. Here, we show that the mammalian target of rapamycin (mTOR) is a crucial regulator of 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP)-induced decidualization in human endometrial stromal cells. The level of mSin1 in mTOR complex 2 (mTORC2) and DEPTOR in mTOR complex 1 (mTORC1) decreases during 8-Br-cAMP-induced decidualization, resulting in decreased mTORC2 activity and increased mTORC1 activity. Notably, DEPTOR displacement increases the association between raptor and insulin receptor substrate-1 (IRS-1), facilitating IRS-1 phosphorylation at serine 636/639. Finally, both S473 and T308 phosphorylation of Akt are reduced during decidualization, followed by a decrease in forkhead box O1 (FOXO1) phosphorylation and an increase in the mRNA levels of the decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1). Taken together, our findings reveal a critical role for mTOR in decidualization, involving the differential regulation of mTORC1 and mTORC2.

SUBMITTER: Baek MO

PROVIDER: S-EPMC6206090 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Baek Mi-Ock MO Song Hae-In HI Han Joong-Soo JS Yoon Mee-Sup MS

Experimental & molecular medicine 20181030 10

Human endometrium decidualization, a differentiation process involving biochemical and morphological changes, is a prerequisite for embryo implantation and successful pregnancy. Here, we show that the mammalian target of rapamycin (mTOR) is a crucial regulator of 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP)-induced decidualization in human endometrial stromal cells. The level of mSin1 in mTOR complex 2 (mTORC2) and DEPTOR in mTOR complex 1 (mTORC1) decreases during 8-Br-cAMP-induced d ...[more]

PMID: 30374127

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Project description:BACKGROUND:The mechanistic target of rapamycin (mTOR) pathway is a potential target to inhibit pathologic processes in choroidal neovascularization. However, the exact role of mTOR signaling in the development of CNV remains obscure. In this study, we assessed the role of mTORC1 and mTORC2 as well as the effect of rapamycin (sirolimus) on choroidal neovascularization (CNV) in a laser-induced mouse model. METHODS:In experiment A, we observed the natural course of CNV development and the dynamics of mTOR-related proteins during the 12?days after the laser injury. The expression of mTOR-related proteins was evaluated using Western blot (WB). Cryosections of CNV-induced mice were immunostained for the visualization of the vascular and extravascular components of the CNV. Experiment B was performed to confirm the critical period of mTOR signaling in the development of laser-induced CNV, we administered rapamycin before and/or during the active period of mTOR complexes. WB and immunofluorescence staining was performed to evaluate the mode of action and the effect of mTOR inhibition on CNV development. RESULTS:In experiment A, we detected high levels of p-mTOR S2448 and p-mTOR S2481 from the 5th to 12th day of laser injury. Immunofluorescence imaging of cryosections of mice sacrificed on day 7 revealed greater co-immunoreactivity of p-mTOR S2448 positive cells with CD11b and F4/80, while p-mTOR S2481 positive cells showed colocalization with CD31, ?-SMA, and cytokeratin. In experiment B, rapamycin injection during the active period of mTOR signaling demonstrated near-complete inhibition of CNV lesion as well as significant induction of autophagy. CONCLUSION:Our study suggests the mTOR as a critical player during CNV development in laser-induced mouse model through differentially acting with the mTORC1 and mTORC2. mTORC1 activity was high predominantly in inflammatory cells in CNV lesion, while mTORC2 activity was higher in vascular components and the RPE.

Dataset Information

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

Publications

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

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