Nitration of protein phosphatase 2A increases via Epac1/PLCε/CaMKII/HDAC5/iNOS cascade in human endometrial stromal cell decidualization

So Young Lee; Yun Young Lee; Joong Sub Choi; Kyeong Soo Kim; Do Sik Min; Shin Young Park; Joong Soo Han

doi:10.1096/fj.202001212R

Nitration of protein phosphatase 2A increases via Epac1/PLCε/CaMKII/HDAC5/iNOS cascade in human endometrial stromal cell decidualization

So Young Lee, Yun Young Lee, Joong Sub Choi, Kyeong Soo Kim, Do Sik Min, Shin Young Park, Joong Soo Han

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

Abstract

Decidualization of the endometrial stroma is an essential differentiation process for embryo implantation and maintenance of pregnancy. We previously reported that protein phosphatase 2A (PP2A) acts as a key mediator during cAMP-induced decidualization of human endometrial stromal cells (hESCs). However, the mechanism underlying its activation has remained obscure in hESCs. In the present study, we aimed to reveal the mechanism that induces the nitration of PP2A catalytic subunit (PP2Ac) during cAMP-induced decidualization of hESCs. First, cAMP-induced PP2Ac nitration was significantly repressed using L-NAME, an inhibitor of nitric oxide synthase (NOS). Among several NOS isoforms, only inducible NOS (iNOS) was highly expressed in hESCs, indicating that iNOS directly induces the nitration of PP2Ac. Second, cAMP-induced iNOS expression and PP2Ac nitration were decreased by treatment with TSA, an inhibitor of histone deacetylase 5 (HDAC5). cAMP-induced phosphorylation of CaMKII and HDAC5 was suppressed by treatment with U73122 (an inhibitor of phospholipase C) or transfection of PLCε siRNA. Finally, small G protein Rap1 and its guanine nucleotide exchange factor Epac1 were found to be involved in cAMP-induced PP2A activation. Taken together, our results suggest that PP2Ac nitration during cAMP-induced decidualization of hESCs is induced through the Epac1-Rap1-PLCε-CaMKII-HDAC5-iNOS signaling pathway.

Original language	English
Pages (from-to)	14407-14423
Number of pages	17
Journal	FASEB Journal
Volume	34
Issue number	11
DOIs	https://doi.org/10.1096/fj.202001212R
Publication status	Published - 2020 Nov 1

Bibliographical note

Funding Information:
We thank Pyung Sun Cho for comments regarding calcium imaging. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF‐2016R1A2B4015358) and an NRF grant funded by the Korean government (MSIP) (2019R1A2B5B01069443). In addition, this work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C0611).

Funding Information:
We thank Pyung Sun Cho for comments regarding calcium imaging. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2016R1A2B4015358) and an NRF grant funded by the Korean government (MSIP) (2019R1A2B5B01069443). In addition, this work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C0611).

Publisher Copyright:
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology

All Science Journal Classification (ASJC) codes

Biotechnology
Biochemistry
Molecular Biology
Genetics

Access to Document

10.1096/fj.202001212R

Cite this

@article{e71de56dc35b486ebb82c8bc7cb16d00,

title = "Nitration of protein phosphatase 2A increases via Epac1/PLCε/CaMKII/HDAC5/iNOS cascade in human endometrial stromal cell decidualization",

abstract = "Decidualization of the endometrial stroma is an essential differentiation process for embryo implantation and maintenance of pregnancy. We previously reported that protein phosphatase 2A (PP2A) acts as a key mediator during cAMP-induced decidualization of human endometrial stromal cells (hESCs). However, the mechanism underlying its activation has remained obscure in hESCs. In the present study, we aimed to reveal the mechanism that induces the nitration of PP2A catalytic subunit (PP2Ac) during cAMP-induced decidualization of hESCs. First, cAMP-induced PP2Ac nitration was significantly repressed using L-NAME, an inhibitor of nitric oxide synthase (NOS). Among several NOS isoforms, only inducible NOS (iNOS) was highly expressed in hESCs, indicating that iNOS directly induces the nitration of PP2Ac. Second, cAMP-induced iNOS expression and PP2Ac nitration were decreased by treatment with TSA, an inhibitor of histone deacetylase 5 (HDAC5). cAMP-induced phosphorylation of CaMKII and HDAC5 was suppressed by treatment with U73122 (an inhibitor of phospholipase C) or transfection of PLCε siRNA. Finally, small G protein Rap1 and its guanine nucleotide exchange factor Epac1 were found to be involved in cAMP-induced PP2A activation. Taken together, our results suggest that PP2Ac nitration during cAMP-induced decidualization of hESCs is induced through the Epac1-Rap1-PLCε-CaMKII-HDAC5-iNOS signaling pathway.",

author = "Lee, {So Young} and Lee, {Yun Young} and Choi, {Joong Sub} and Kim, {Kyeong Soo} and Min, {Do Sik} and Park, {Shin Young} and Han, {Joong Soo}",

note = "Funding Information: We thank Pyung Sun Cho for comments regarding calcium imaging. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF‐2016R1A2B4015358) and an NRF grant funded by the Korean government (MSIP) (2019R1A2B5B01069443). In addition, this work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C0611). Funding Information: We thank Pyung Sun Cho for comments regarding calcium imaging. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2016R1A2B4015358) and an NRF grant funded by the Korean government (MSIP) (2019R1A2B5B01069443). In addition, this work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C0611). Publisher Copyright: {\textcopyright} 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology",

year = "2020",

month = nov,

day = "1",

doi = "10.1096/fj.202001212R",

language = "English",

volume = "34",

pages = "14407--14423",

journal = "FASEB Journal",

issn = "0892-6638",

publisher = "FASEB",

number = "11",

}

TY - JOUR

T1 - Nitration of protein phosphatase 2A increases via Epac1/PLCε/CaMKII/HDAC5/iNOS cascade in human endometrial stromal cell decidualization

AU - Lee, So Young

AU - Lee, Yun Young

AU - Choi, Joong Sub

AU - Kim, Kyeong Soo

AU - Min, Do Sik

AU - Park, Shin Young

AU - Han, Joong Soo

N1 - Funding Information: We thank Pyung Sun Cho for comments regarding calcium imaging. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF‐2016R1A2B4015358) and an NRF grant funded by the Korean government (MSIP) (2019R1A2B5B01069443). In addition, this work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C0611). Funding Information: We thank Pyung Sun Cho for comments regarding calcium imaging. This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2016R1A2B4015358) and an NRF grant funded by the Korean government (MSIP) (2019R1A2B5B01069443). In addition, this work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI19C0611). Publisher Copyright: © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology

PY - 2020/11/1

Y1 - 2020/11/1

N2 - Decidualization of the endometrial stroma is an essential differentiation process for embryo implantation and maintenance of pregnancy. We previously reported that protein phosphatase 2A (PP2A) acts as a key mediator during cAMP-induced decidualization of human endometrial stromal cells (hESCs). However, the mechanism underlying its activation has remained obscure in hESCs. In the present study, we aimed to reveal the mechanism that induces the nitration of PP2A catalytic subunit (PP2Ac) during cAMP-induced decidualization of hESCs. First, cAMP-induced PP2Ac nitration was significantly repressed using L-NAME, an inhibitor of nitric oxide synthase (NOS). Among several NOS isoforms, only inducible NOS (iNOS) was highly expressed in hESCs, indicating that iNOS directly induces the nitration of PP2Ac. Second, cAMP-induced iNOS expression and PP2Ac nitration were decreased by treatment with TSA, an inhibitor of histone deacetylase 5 (HDAC5). cAMP-induced phosphorylation of CaMKII and HDAC5 was suppressed by treatment with U73122 (an inhibitor of phospholipase C) or transfection of PLCε siRNA. Finally, small G protein Rap1 and its guanine nucleotide exchange factor Epac1 were found to be involved in cAMP-induced PP2A activation. Taken together, our results suggest that PP2Ac nitration during cAMP-induced decidualization of hESCs is induced through the Epac1-Rap1-PLCε-CaMKII-HDAC5-iNOS signaling pathway.

AB - Decidualization of the endometrial stroma is an essential differentiation process for embryo implantation and maintenance of pregnancy. We previously reported that protein phosphatase 2A (PP2A) acts as a key mediator during cAMP-induced decidualization of human endometrial stromal cells (hESCs). However, the mechanism underlying its activation has remained obscure in hESCs. In the present study, we aimed to reveal the mechanism that induces the nitration of PP2A catalytic subunit (PP2Ac) during cAMP-induced decidualization of hESCs. First, cAMP-induced PP2Ac nitration was significantly repressed using L-NAME, an inhibitor of nitric oxide synthase (NOS). Among several NOS isoforms, only inducible NOS (iNOS) was highly expressed in hESCs, indicating that iNOS directly induces the nitration of PP2Ac. Second, cAMP-induced iNOS expression and PP2Ac nitration were decreased by treatment with TSA, an inhibitor of histone deacetylase 5 (HDAC5). cAMP-induced phosphorylation of CaMKII and HDAC5 was suppressed by treatment with U73122 (an inhibitor of phospholipase C) or transfection of PLCε siRNA. Finally, small G protein Rap1 and its guanine nucleotide exchange factor Epac1 were found to be involved in cAMP-induced PP2A activation. Taken together, our results suggest that PP2Ac nitration during cAMP-induced decidualization of hESCs is induced through the Epac1-Rap1-PLCε-CaMKII-HDAC5-iNOS signaling pathway.

UR - http://www.scopus.com/inward/record.url?scp=85091733162&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85091733162&partnerID=8YFLogxK

U2 - 10.1096/fj.202001212R

DO - 10.1096/fj.202001212R

M3 - Article

C2 - 33000885

AN - SCOPUS:85091733162

SN - 0892-6638

VL - 34

SP - 14407

EP - 14423

JO - FASEB Journal

JF - FASEB Journal

IS - 11

ER -

Nitration of protein phosphatase 2A increases via Epac1/PLCε/CaMKII/HDAC5/iNOS cascade in human endometrial stromal cell decidualization

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this