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      CDC20 inhibitor Apcin inhibits embryo implantation in vivo and in vitro

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          Abstract

          For successful implantation, endometrial receptivity must be established. The high expression of CDC20 in many kinds of malignant tumours has been reported, and it is related to the occurrence and development of tumours. According to these functions, we think that CDC20 may also play important roles in the process of embryo implantation. To prove our hypothesis, we observed the distribution and expression of CDC20 in mouse and human early pregnancy. The effect of E2 and/or P4 on the expression of CDC20 in human endometrial cells was detected by Western blot. To further explore whether CDC20 is an important factor in adhesion and proliferation. The results showed that the expression of CDC20 in the uterus and menstrual cycle of early pregnant mice was spatiotemporal. E2 can promote the expression of CDC20. On the contrary, P4 and E2 + P4 inhibited the expression of CDC20. We also detected the proliferation and adhesion of human endometrial cells. We found that the inhibition of CDC20 with its inhibitor Apcin could reduce the adhesion rate and proliferation ability to RL95‐2 and HEC‐1A cells, respectively. Inhibiting CDC20 by Apcin could interfere the embryo implantation of mouse. It is suggested that CDC20 may play an important role in the process of embryo implantation.

          Significance of the study

          Embryo implantation is an extremely complex and delicate process, including identification, localisation, adhesion and invasion between embryo and endometrium. Studies have shown the process of embryo implantation is very similar to that of tumour invasion. CDC20 is a cancer‐promoting factor. We found CDC20 is spatially and spatially expressed in mouse and human menstrual cycles and is regulated by oestrogen and progesterone. Apcin can inhibit the adhesion of JAR cells and embryo implantation of mouse. CDC20 may provide a new way to improve the success rate of assisted reproduction.

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          Most cited references20

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          Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C.

          Protein machines are multi-subunit protein complexes that orchestrate highly regulated biochemical tasks. An example is the anaphase-promoting complex/cyclosome (APC/C), a 13-subunit ubiquitin ligase that initiates the metaphase-anaphase transition and mitotic exit by targeting proteins such as securin and cyclin B1 for ubiquitin-dependent destruction by the proteasome. Because blocking mitotic exit is an effective approach for inducing tumour cell death, the APC/C represents a potential novel target for cancer therapy. APC/C activation in mitosis requires binding of Cdc20 (ref. 5), which forms a co-receptor with the APC/C to recognize substrates containing a destruction box (D-box). Here we demonstrate that we can synergistically inhibit APC/C-dependent proteolysis and mitotic exit by simultaneously disrupting two protein-protein interactions within the APC/C-Cdc20-substrate ternary complex. We identify a small molecule, called apcin (APC inhibitor), which binds to Cdc20 and competitively inhibits the ubiquitylation of D-box-containing substrates. Analysis of the crystal structure of the apcin-Cdc20 complex suggests that apcin occupies the D-box-binding pocket on the side face of the WD40-domain. The ability of apcin to block mitotic exit is synergistically amplified by co-addition of tosyl-l-arginine methyl ester, a small molecule that blocks the APC/C-Cdc20 interaction. This work suggests that simultaneous disruption of multiple, weak protein-protein interactions is an effective approach for inactivating a protein machine.
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            Molecular architecture and mechanism of the anaphase-promoting complex.

            The ubiquitination of cell cycle regulatory proteins by the anaphase-promoting complex/cyclosome (APC/C) controls sister chromatid segregation, cytokinesis and the establishment of the G1 phase of the cell cycle. The APC/C is an unusually large multimeric cullin-RING ligase. Its activity is strictly dependent on regulatory coactivator subunits that promote APC/C-substrate interactions and stimulate its catalytic reaction. Because the structures of many APC/C subunits and their organization within the assembly are unknown, the molecular basis for these processes is poorly understood. Here, from a cryo-electron microscopy reconstruction of a human APC/C-coactivator-substrate complex at 7.4 Å resolution, we have determined the complete secondary structural architecture of the complex. With this information we identified protein folds for structurally uncharacterized subunits, and the definitive location of all 20 APC/C subunits within the 1.2 MDa assembly. Comparison with apo APC/C shows that the coactivator promotes a profound allosteric transition involving displacement of the cullin-RING catalytic subunits relative to the degron-recognition module of coactivator and APC10. This transition is accompanied by increased flexibility of the cullin-RING subunits and enhanced affinity for UBCH10-ubiquitin, changes which may contribute to coactivator-mediated stimulation of APC/C E3 ligase activity.
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              Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study.

              Is there a relationship between serum progesterone (P) and endometrial volume on the day of embryo transfer (ET) with ongoing pregnancy rate (OPR) in artificial endometrium preparation cycles?
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                Author and article information

                Contributors
                147554241@qq.com
                Journal
                Cell Biochem Funct
                Cell Biochem. Funct
                10.1002/(ISSN)1099-0844
                CBF
                Cell Biochemistry and Function
                John Wiley and Sons Inc. (Hoboken )
                0263-6484
                1099-0844
                26 May 2020
                August 2020
                : 38
                : 6 ( doiID: 10.1002/cbf.v38.6 )
                : 810-816
                Affiliations
                [ 1 ] Department of Gynecology and Obstetrics First Affiliated Hospital of Dalian Medical University Dalian China
                Author notes
                [*] [* ] Correspondence

                Xiaojing Sun, Department of Gynecology and Obstetrics, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116044, China.

                Email: 147554241@ 123456qq.com

                Author information
                https://orcid.org/0000-0001-8191-0556
                Article
                CBF3550
                10.1002/cbf.3550
                7496523
                32458533
                dc4b9c4c-fe02-46d4-a3a5-9767491d6b6e
                © 2020 The Authors. Cell Biochemistry and Function published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 January 2020
                : 09 April 2020
                : 27 April 2020
                Page count
                Figures: 4, Tables: 0, Pages: 7, Words: 4276
                Funding
                Funded by: Dalian Medical Science Research Project
                Award ID: 18Z2003
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                August 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.0 mode:remove_FC converted:11.09.2020

                adhesion,apcin,cdc20,implantation,proliferation
                adhesion, apcin, cdc20, implantation, proliferation

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