TORC2/3-mediated DUSP1 upregulation is essential for human decidualization

in Reproduction
View More View Less
  • 1 Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, People’s Republic of China
  • 2 Department of Gynecology and Obstetrics, The First People’s Hospital of Guangzhou, Guangzhou, People’s Republic of China
  • 3 Department of Gynecology and Obstetrics, The First People’s Hospital of Yangzhou, Yangzhou Medical University, Yangzhou, People’s Republic of China
  • 4 Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacy, Fudan University, Shanghai, People’s Republic of China

Correspondence should be addressed to M Du; Email: dmrlq1973@sina.cn

*(C Xu, W Zhao and Xi Huang contributed equally to this work)

Restricted access

Decidualization is the functional transformation process of endometrium in response to ovarian steroids dedicated to support embryo development. Defective decidualization is closely associated with various pregnancy complications such as recurrent miscarriage (RM). Dual specificity MAPK phosphatases (MKPs) are a family of phosphatases specifically regulating mitogen-activated protein kinase (MAPK) signaling with dual specificity for threonine and tyrosine. Here, using RNA-seq,we found that dual specificity phosphatase 1 (DUSP1) expression was prominently elevated among the MKP family members in db-cAMP treated primary human endometrial stromal cells (ESCs). We verified that its induction by db-cAMP in ESCs was in a dose- and time-dependent manner and that primary human decidual stromal cells (DSCs) present higher expression of DUSP1 than ESCs. A protein kinase A (PKA) inhibitor H-89 abolished its induction in ESCs, but not ESI-09, an EPAC1/2 inhibitor. Knock-down of TORC2/3 but not CREB by siRNA in ESCs diminished its induction by db-cAMP. Furthermore, knock-down of DUSP1, as well as TORC2/3 by siRNA caused abnormal activation of JNK during db-cAMP induction in ESCs, accompanied by decreased IGFBP1 expression, an ESC decidualization indicator, which could be fully rescued by a JNK inhibitor SP600125. In addition, Western blot showed that DUSP1 expression was reduced in the DSCs of patients with RM, along with JNK overactivation and decreased IGFBP1 expression. In conclusion, our results demonstrated that TORC2/3-mediated DUSP1 upregulation in response to the cAMP/PKA signaling safeguards IGFBP1 expression via restraining JNK activity, indicating its involvement in ESC decidualization, and that aberrant expression of DUSP1 in DSCs might engage in the pathogenesis of RM.

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 160 160 154
Full Text Views 17 17 17
PDF Downloads 29 29 29
  • Bole-Feysot C, Goffin V, Edery M, Binart N & Kelly PA 1998 Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocrine Reviews 19 2252 68. (https://doi.org/10.1210/edrv.19.3.0334)

    • Search Google Scholar
    • Export Citation
  • Boutros T, Chevet E & Metrakos P 2008 Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacological Reviews 60 261310. (https://doi.org/10.1124/pr.107.00106)

    • Search Google Scholar
    • Export Citation
  • Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P, Milad M & Wei J 2019 Endometriosis. Endocrine Reviews 40 10481079. (https://doi.org/10.1210/er.2018-00242)

    • Search Google Scholar
    • Export Citation
  • Burgun C, Esteve L, Humblot N, Aunis D & Zwiller J 2000 Cyclic AMP-elevating agents induce the expression of MAP kinase phosphatase-1 in PC12 cells. FEBS Letters 484 1891 93. (https://doi.org/10.1016/s0014-5793(0002153-0)

    • Search Google Scholar
    • Export Citation
  • Canettieri G, Coni S, Della Guardia M, Nocerino V, Antonucci L, Di Magno L, Screaton R, Screpanti I, Giannini G & Gulino A 2009 The coactivator CRTC1 promotes cell proliferation and transformation via AP-1. PNAS 106 144514 50. (https://doi.org/10.1073/pnas.0808749106)

    • Search Google Scholar
    • Export Citation
  • Carlezon Jr WA, Duman RS & Nestler EJ 2005 The many faces of CREB. Trends in Neurosciences 28 4364 4 5. (https://doi.org/10.1016/j.tins.2005.06.005)

    • Search Google Scholar
    • Export Citation
  • Comb M, Birnberg NC, Seasholtz A, Herbert E & Goodman HM 1986 A cyclic AMP- and phorbol ester-inducible DNA element. Nature 323 35335 6. (https://doi.org/10.1038/323353a0)

    • Search Google Scholar
    • Export Citation
  • Conkright MD, Canettieri G, Screaton R, Guzman E, Miraglia L, Hogenesch JB & Montminy M 2003 TORCs: transducers of regulated CREB activity. Molecular Cell 12 4134 23. (https://doi.org/10.1016/j.molcel.2003.08.013)

    • Search Google Scholar
    • Export Citation
  • Dentin R, Hedrick S, Xie J, Yates J 3rd & Montminy M 2008 Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319 1402140 5. (https://doi.org/10.1126/science.1151363)

    • Search Google Scholar
    • Export Citation
  • Dickinson RJ & Keyse SM 2006 Diverse physiological functions for dual-specificity MAP kinase phosphatases. Journal of Cell Science 119 460746 15. (https://doi.org/10.1242/jcs.03266)

    • Search Google Scholar
    • Export Citation
  • Dimitriadis E, Menkhorst E, Saito S, Kutteh WH & Brosens JJ 2020 Recurrent pregnancy loss. Nature Reviews: Disease Primers 6 98. (https://doi.org/10.1038/s41572-020-00228-z)

    • Search Google Scholar
    • Export Citation
  • Garrido-Gomez T, Dominguez F, Quinonero A, Diaz-Gimeno P, Kapidzic M, Gormley M, Ona K, Padilla-Iserte P, Mcmaster M & Genbacev O et al. 2017 Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology. PNAS 114 E8468–E8477. (https://doi.org/10.1073/pnas.1706546114)

    • Search Google Scholar
    • Export Citation
  • Gellersen B & Brosens JJ 2014 Cyclic decidualization of the human endometrium in reproductive health and failure. Endocrine Reviews 35 851905. (https://doi.org/10.1210/er.2014-1045)

    • Search Google Scholar
    • Export Citation
  • Hai T, Wolfgang CD, Marsee DK, Allen AE & Sivaprasad U 1999 ATF3 and stress responses. Gene Expression 7 3213 3 5.

  • Johannessen M, Delghandi MP & Moens U 2004 What turns CREB on? Cellular Signalling 16 121112 27. (https://doi.org/10.1016/j.cellsig.2004.05.001)

    • Search Google Scholar
    • Export Citation
  • Kang Y, Nagaraja AS, Armaiz-Pena GN, Dorniak PL, Hu W, Rupaimoole R, Liu T, Gharpure KM, Previs RA & Hansen JM et al. 2016 Adrenergic stimulation of DUSP1 impairs chemotherapy response in ovarian cancer. Clinical Cancer Research 22 171317 24. (https://doi.org/10.1158/1078-0432.CCR-15-1275)

    • Search Google Scholar
    • Export Citation
  • Kim D, Langmead B & Salzberg SL 2015 HISAT: a fast spliced aligner with low memory requirements. Nature Methods 12 3573 60. (https://doi.org/10.1038/nmeth.3317)

    • Search Google Scholar
    • Export Citation
  • Kim JH, Hong AR, Kim YH, Yoo H, Kang SW, Chang SE & Song Y 2020 JNK suppresses melanogenesis by interfering with CREB-regulated transcription coactivator 3-dependent MITF expression. Theranostics 10 40174029. (https://doi.org/10.7150/thno.41502)

    • Search Google Scholar
    • Export Citation
  • Kusama K, Yoshie M, Tamura K, Kodaka Y, Hirata A, Sakurai T, Bai H, Imakawa K, Nishi H & Isaka K et al. 2013 Regulation of decidualization in human endometrial stromal cells through exchange protein directly activated by cyclic AMP (Epac). Placenta 34 2122 2 1. (https://doi.org/10.1016/j.placenta.2012.12.017)

    • Search Google Scholar
    • Export Citation
  • Kwak SP, Hakes DJ, Martell KJ & Dixon JE 1994 Isolation and characterization of a human dual specificity protein-tyrosine phosphatase gene. Journal of Biological Chemistry 269 35963 604. (https://doi.org/10.1016/S0021-9258(1741905-3)

    • Search Google Scholar
    • Export Citation
  • Langmead B & Salzberg SL 2012 Fast gapped-read alignment with Bowtie 2. Nature Methods 9 357359. (https://doi.org/10.1038/nmeth.1923)

  • Leitao B, Jones MC, Fusi L, Higham J, Lee Y, Takano M, Goto T, Christian M, Lam EW & Brosens JJ 2010 Silencing of the JNK pathway maintains progesterone receptor activity in decidualizing human endometrial stromal cells exposed to oxidative stress signals. FASEB Journal 24 154115 51. (https://doi.org/10.1096/fj.09-149153)

    • Search Google Scholar
    • Export Citation
  • Li B & Dewey CN 2011 RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12 323. (https://doi.org/10.1186/1471-2105-12-323)

    • Search Google Scholar
    • Export Citation
  • Li R, Li Y, Kristiansen K & Wang J 2008 SOAP: short oligonucleotide alignment program. Bioinformatics 24 71371 4. (https://doi.org/10.1093/bioinformatics/btn025)

    • Search Google Scholar
    • Export Citation
  • Liu Y, Shepherd EG & Nelin LD 2007 MAPK phosphatases – regulating the immune response. Nature Reviews: Immunology 7 2022 12. (https://doi.org/10.1038/nri2035)

    • Search Google Scholar
    • Export Citation
  • Mazur EC, Vasquez YM, Li X, Kommagani R, Jiang L, Chen R, Lanz RB, Kovanci E, Gibbons WE & Demayo FJ 2015 Progesterone receptor transcriptome and cistrome in decidualized human endometrial stromal cells. Endocrinology 156 223922 53. (https://doi.org/10.1210/en.2014-1566)

    • Search Google Scholar
    • Export Citation
  • Plevin R, Malarkey K, Aidulis D, Mclees A & Gould GW 1997 Cyclic AMP inhibitors inhibits PDGF-stimulated mitogen-activated protein kinase activity in rat aortic smooth muscle cells via inactivation of c-Raf-1 kinase and induction of MAP kinase phosphatase-1. Cellular Signalling 9 32332 8. (https://doi.org/10.1016/s0898-6568(9600193-3)

    • Search Google Scholar
    • Export Citation
  • Romero R, Dey SK & Fisher SJ 2014 Preterm labor: one syndrome, many causes. Science 345 76076 5. (https://doi.org/10.1126/science.1251816)

  • Shaw KJ, Do YS, Kjos S, Anderson PW, Shinagawa T, Dubeau L & Hsueh WA 1989 Human decidua is a major source of renin. Journal of Clinical Investigation 83 208520 92. (https://doi.org/10.1172/JCI114121)

    • Search Google Scholar
    • Export Citation
  • Short JM, Wynshaw-Boris A, Short HP & Hanson RW 1986 Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. II. Identification of cAMP and glucocorticoid regulatory domains. Journal of Biological Chemistry 261 9721972 6. (https://doi.org/10.1016/S0021-9258(1867574-X)

    • Search Google Scholar
    • Export Citation
  • Song Y, Altarejos J, Goodarzi MO, Inoue H, Guo X, Berdeaux R, Kim JH, Goode J, Igata M & Paz JC et al. 2010 CRTC3 links catecholamine signalling to energy balance. Nature 468 9339 39. (https://doi.org/10.1038/nature09564)

    • Search Google Scholar
    • Export Citation
  • Suwanichkul A, Depaolis LA, Lee PD & Powell DR 1993 Identification of a promoter element which participates in cAMP-stimulated expression of human insulin-like growth factor-binding protein-1. Journal of Biological Chemistry 268 9730973 6. (https://doi.org/10.1016/S0021-9258(1898409-7)

    • Search Google Scholar
    • Export Citation
  • Wagner EF & Nebreda AR 2009 Signal integration by JNK and p38 MAPK pathways in cancer development. Nature Reviews: Cancer 9 5375 49. (https://doi.org/10.1038/nrc2694)

    • Search Google Scholar
    • Export Citation
  • Yin X, Pavone ME, Lu Z, Wei J & Kim JJ 2012 Increased activation of the PI3K/AKT pathway compromises decidualization of stromal cells from endometriosis. Journal of Clinical Endocrinology and Metabolism 97 E35E 43. (https://doi.org/10.1210/jc.2011-1527)

    • Search Google Scholar
    • Export Citation