{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T21:48:26Z","timestamp":1782337706773,"version":"3.54.5"},"reference-count":82,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["390921723"],"award-info":[{"award-number":["390921723"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1\/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (\u03b2-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.<\/jats:p>","DOI":"10.3390\/cells10092214","type":"journal-article","created":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T09:53:23Z","timestamp":1630058003000},"page":"2214","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Functional Analysis of p21Cip1\/CDKN1A and Its Family Members in Trophoblastic Cells of the Placenta and Its Roles in Preeclampsia"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4304-0160","authenticated-orcid":false,"given":"Nina-Naomi","family":"Kreis","sequence":"first","affiliation":[{"name":"Obstetrics and Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Friemel","sequence":"additional","affiliation":[{"name":"Obstetrics and Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6919-9394","authenticated-orcid":false,"given":"Lukas","family":"Jennewein","sequence":"additional","affiliation":[{"name":"Obstetrics and Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira Catharina","family":"Hoock","sequence":"additional","affiliation":[{"name":"Obstetrics and Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Elisabeth","family":"Hentrich","sequence":"additional","affiliation":[{"name":"Obstetrics and Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Nowak","sequence":"additional","affiliation":[{"name":"Medical Practice for Gynecology and Obstetrics, Mainzer Landstr. 265, 60326 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Louwen","sequence":"additional","affiliation":[{"name":"Obstetrics and Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0694-0565","authenticated-orcid":false,"given":"Juping","family":"Yuan","sequence":"additional","affiliation":[{"name":"Obstetrics and Prenatal Medicine, Department of Gynecology and Obstetrics, University Hospital Frankfurt, J. W. Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0140-6736(10)60279-6","article-title":"Pre-eclampsia","volume":"376","author":"Steegers","year":"2010","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41581-019-0119-6","article-title":"Pre-eclampsia: Pathogenesis, novel diagnostics and therapies","volume":"15","author":"Phipps","year":"2019","journal-title":"Nat Rev. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1016\/0002-9378(89)90665-0","article-title":"Preeclampsia: An endothelial cell disorder","volume":"161","author":"Roberts","year":"1989","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s11906-015-0595-4","article-title":"Preeclampsia: Syndrome or Disease?","volume":"17","author":"Myatt","year":"2015","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jri.2017.09.006","article-title":"Historical evolution of ideas on eclampsia\/preeclampsia: A proposed optimistic view of preeclampsia","volume":"123","author":"Robillard","year":"2017","journal-title":"J. Reprod. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.2215\/CJN.12081115","article-title":"Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines","volume":"11","author":"Phipps","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0002-9378(16)32330-4","article-title":"Syndrome of hemolysis, elevated liver enzymes, and low platelet count: A severe consequence of hypertension in pregnancy","volume":"142","author":"Weinstein","year":"1982","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1161\/CIRCRESAHA.118.313276","article-title":"Preeclampsia: Pathophysiology, Challenges, and Perspectives","volume":"124","author":"Rana","year":"2019","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"dev163428","DOI":"10.1242\/dev.163428","article-title":"Development of the human placenta","volume":"146","author":"Turco","year":"2019","journal-title":"Development"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"910751","DOI":"10.1155\/2014\/910751","article-title":"Genetic aspects of preeclampsia and the HELLP syndrome","volume":"2014","author":"Haram","year":"2014","journal-title":"J. Pregnancy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"190","DOI":"10.3389\/fgene.2013.00190","article-title":"Human placental trophoblast invasion and differentiation: A particular focus on Wnt signaling","volume":"4","author":"Knofler","year":"2013","journal-title":"Front Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1242\/dev.113.3.767","article-title":"E-cadherin expression during the differentiation of human trophoblasts","volume":"113","author":"Coutifaris","year":"1991","journal-title":"Development"},{"key":"ref_13","first-page":"76","article-title":"Fusion of cytotrophoblast with syncytiotrophoblast in the human placenta: Factors involved in syncytialization","volume":"5","author":"Gauster","year":"2008","journal-title":"J. Reprod. Med. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1093\/humupd\/dmab015","article-title":"Cell dynamics in human villous trophoblast","volume":"27","author":"Aplin","year":"2021","journal-title":"Hum. Reprod. Update"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1007\/s00018-019-03104-6","article-title":"Human placenta and trophoblast development: Key molecular mechanisms and model systems","volume":"76","author":"Knofler","year":"2019","journal-title":"Cell Mol. Life Sci."},{"key":"ref_16","first-page":"37","article-title":"Beyond pregnancy: Modulation of trophoblast invasion and its consequences for fetal growth and long-term children\u2019s health","volume":"104\u2013105","author":"Lash","year":"2014","journal-title":"J. Reprod. Immunol."},{"key":"ref_17","first-page":"372","article-title":"Endothelial dysfunction and preeclampsia: Role of oxidative stress","volume":"5","author":"Prada","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.placenta.2007.11.002","article-title":"Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast","volume":"29","author":"Heazell","year":"2008","journal-title":"Placenta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ajog.2005.07.039","article-title":"Apoptosis and its role in the trophoblast","volume":"195","author":"Huppertz","year":"2006","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1477-7827-2-53","article-title":"The placental problem: Linking abnormal cytotrophoblast differentiation to the maternal symptoms of preeclampsia","volume":"2","author":"Fisher","year":"2004","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1080\/15384101.2015.1120925","article-title":"Coordinating cell proliferation and differentiation: Antagonism between cell cycle regulators and cell type-specific gene expression","volume":"15","author":"Ruijtenberg","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1097\/CCO.0b013e32835b639e","article-title":"p21WAF1 and tumourigenesis: 20 years after","volume":"25","author":"Warfel","year":"2013","journal-title":"Curr. Opin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1038\/onc.2014.133","article-title":"Less understood issues: p21(Cip1) in mitosis and its therapeutic potential","volume":"34","author":"Kreis","year":"2015","journal-title":"Oncogene"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kreis, N.N., Louwen, F., and Yuan, J. (2019). The Multifaceted p21 (Cip1\/Waf1\/CDKN1A) in Cell Differentiation, Migration and Cancer Therapy. Cancers, 11.","DOI":"10.3390\/cancers11091220"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kreis, N.N., Friemel, A., Ritter, A., Roth, S., Rolle, U., Louwen, F., and Yuan, J. (2019). Function of p21 (Cip1\/Waf1\/CDKN1A) in Migration and Invasion of Cancer and Trophoblastic Cells. Cancers, 11.","DOI":"10.3390\/cancers11070989"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1038\/s41596-020-0381-x","article-title":"Establishment and differentiation of long-term trophoblast organoid cultures from the human placenta","volume":"15","author":"Sheridan","year":"2020","journal-title":"Nat. Protoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"34475","DOI":"10.18632\/oncotarget.5922","article-title":"Characterization of adipose-derived stem cells from subcutaneous and visceral adipose tissues and their function in breast cancer cells","volume":"6","author":"Ritter","year":"2015","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s41586-018-0753-3","article-title":"Trophoblast organoids as a model for maternal-fetal interactions during human placentation","volume":"564","author":"Turco","year":"2018","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.stemcr.2018.07.004","article-title":"Self-Renewing Trophoblast Organoids Recapitulate the Developmental Program of the Early Human Placenta","volume":"11","author":"Haider","year":"2018","journal-title":"Stem Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1922","DOI":"10.1194\/jlr.P093427","article-title":"Metabolism of cholesterol and progesterone is differentially regulated in primary trophoblastic subtypes and might be disturbed in recurrent miscarriages","volume":"60","author":"Vondra","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_31","first-page":"203","article-title":"Isolation and culture of term human trophoblast cells","volume":"121","author":"Petroff","year":"2006","journal-title":"Methods Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1E.2.1","DOI":"10.1002\/9780470151808.sc01e02s1","article-title":"Isolation of Mesenchymal Stem Cells from Amniotic Fluid and Placenta","volume":"1","author":"Steigman","year":"2007","journal-title":"Curr. Protoc. Stem Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.radonc.2017.10.028","article-title":"Prognostic impact of RITA expression in patients with anal squamous cell carcinoma treated with chemoradiotherapy","volume":"126","author":"Rodel","year":"2018","journal-title":"Radiother. Oncol. J. Eur. Soc. Ther. Radiol. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1136\/jcp.48.9.876","article-title":"A \u201cquickscore\u201d method for immunohistochemical semiquantitation: Validation for oestrogen receptor in breast carcinomas","volume":"48","author":"Detre","year":"1995","journal-title":"J. Clin. Pathol."},{"key":"ref_35","first-page":"3545","article-title":"Automated quantitation of immunocytochemically localized estrogen receptors in human breast cancer","volume":"50","author":"McClelland","year":"1990","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.placenta.2004.09.009","article-title":"Evaluation of housekeeping genes in placental comparative expression studies","volume":"26","author":"Meller","year":"2005","journal-title":"Placenta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"759","DOI":"10.18632\/oncotarget.595","article-title":"A lesson for cancer research: Placental microarray gene analysis in preeclampsia","volume":"3","author":"Louwen","year":"2012","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Muschol-Steinmetz, C., Friemel, A., Kreis, N.N., Reinhard, J., Yuan, J., and Louwen, F. (2013). Function of survivin in trophoblastic cells of the placenta. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073337"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1006\/excr.1993.1139","article-title":"Establishment and characterization of first trimester human trophoblast cells with extended lifespan","volume":"206","author":"Graham","year":"1993","journal-title":"Exp. Cell Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1093\/humrep\/deg211","article-title":"Nitric oxide inhibits polyamine-induced apoptosis in the human extravillous trophoblast cell line SGHPL-4","volume":"18","author":"Dash","year":"2003","journal-title":"Hum. Reprod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"50215","DOI":"10.18632\/oncotarget.10330","article-title":"Mitotic p21Cip1\/CDKN1A is regulated by cyclin-dependent kinase 1 phosphorylation","volume":"7","author":"Kreis","year":"2016","journal-title":"Oncotarget"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"460","DOI":"10.4161\/cc.8.3.7651","article-title":"Long-term downregulation of Polo-like kinase 1 increases the cyclin-dependent kinase inhibitor p21(WAF1\/CIP1)","volume":"8","author":"Kreis","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1095\/biolreprod.110.083915","article-title":"GCM1 regulation of the expression of syncytin 2 and its cognate receptor MFSD2A in human placenta","volume":"83","author":"Liang","year":"2010","journal-title":"Biol. Reprod."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.placenta.2015.06.011","article-title":"Placental expression of imprinted genes varies with sampling site and mode of delivery","volume":"36","author":"Janssen","year":"2015","journal-title":"Placenta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.1016\/j.placenta.2008.11.009","article-title":"The two stage model of preeclampsia: Variations on the theme","volume":"30","author":"Roberts","year":"2009","journal-title":"Placenta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1161\/HYPERTENSIONAHA.110.153163","article-title":"Inhibition of trophoblast-induced spiral artery remodeling reduces placental perfusion in rat pregnancy","volume":"56","author":"Verlohren","year":"2010","journal-title":"Hypertension"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1530\/REP-10-0221","article-title":"The choriocarcinoma cell line BeWo: Syncytial fusion and expression of syncytium-specific proteins","volume":"140","author":"Orendi","year":"2010","journal-title":"Reproduction"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.bbamcr.2006.11.001","article-title":"Atypical mitogen-activated protein kinases: Structure, regulation and functions","volume":"1773","author":"Coulombe","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1128\/MMBR.00031-10","article-title":"Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases","volume":"75","author":"Cargnello","year":"2011","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sharp, A.N., Heazell, A.E., Baczyk, D., Dunk, C.E., Lacey, H.A., Jones, C.J., Perkins, J.E., Kingdom, J.C., Baker, P.N., and Crocker, I.P. (2014). Preeclampsia is associated with alterations in the p53-pathway in villous trophoblast. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087621"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s00441-007-0511-6","article-title":"Distribution of Notch protein members in normal and preeclampsia-complicated placentas","volume":"330","author":"Cobellis","year":"2007","journal-title":"Cell Tissue Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1016\/j.humpath.2014.02.002","article-title":"Targeted gene analysis: Increased B-cell lymphoma 6 in preeclamptic placentas","volume":"45","author":"Louwen","year":"2014","journal-title":"Hum. Pathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00418-016-1435-6","article-title":"Placental aging and oxidation damage in a tissue micro-array model: An immunohistochemistry study","volume":"146","author":"Londero","year":"2016","journal-title":"Histochem. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fendo.2020.597549","article-title":"CCN3 Signaling Is Differently Regulated in Placental Diseases Preeclampsia and Abnormally Invasive Placenta","volume":"11","author":"Duan","year":"2020","journal-title":"Front Endocrinol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1126\/science.277.5332.1669","article-title":"Regulation of human placental development by oxygen tension","volume":"277","author":"Genbacev","year":"1997","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"C968","DOI":"10.1152\/ajpcell.00154.2010","article-title":"Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts","volume":"299","author":"Chen","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/ni1245","article-title":"BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells","volume":"6","author":"Phan","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_58","first-page":"787","article-title":"Tpbpa-Cre-mediated deletion of TFAP2C leads to deregulation of Cdkn1a, Akt1 and the ERK pathway, causing placental growth arrest","volume":"143","author":"Sharma","year":"2016","journal-title":"Development"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4376","DOI":"10.1210\/en.2008-1645","article-title":"Activator protein-2 impairs the invasion of a human extravillous trophoblast cell line","volume":"150","author":"Kotani","year":"2009","journal-title":"Endocrinology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.biocel.2015.02.002","article-title":"The hypoxia-induced microRNA-130a controls pulmonary smooth muscle cell proliferation by directly targeting CDKN1A","volume":"61","author":"Brock","year":"2015","journal-title":"Int. J Biochem. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3892\/mmr.2015.3414","article-title":"Deregulated microRNA species in the plasma and placenta of patients with preeclampsia","volume":"12","author":"Yang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S0925-4439(03)00043-7","article-title":"Hypoxia alters expression and function of syncytin and its receptor during trophoblast cell fusion of human placental BeWo cells: Implications for impaired trophoblast syncytialisation in pre-eclampsia","volume":"1638","author":"Kudo","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/molehr\/gau113","article-title":"A novel regulator of human villous trophoblast fusion: The Kruppel-like factor 6","volume":"21","author":"Racca","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-020-01848-8","article-title":"Transcriptomic analysis reveals differential gene expression, alternative splicing, and novel exons during mouse trophoblast stem cell differentiation","volume":"11","author":"Ullah","year":"2020","journal-title":"Stem. Cell Res. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1007\/s00018-017-2695-6","article-title":"Downregulation of p53 drives autophagy during human trophoblast differentiation","volume":"75","author":"Gauster","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.celrep.2017.10.019","article-title":"Fine-Tuned and Cell-Cycle-Restricted Expression of Fusogenic Protein Syncytin-2 Maintains Functional Placental Syncytia","volume":"21","author":"Lu","year":"2017","journal-title":"Cell Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1177\/1933719111404608","article-title":"Reduced expression of both syncytin 1 and syncytin 2 correlates with severity of preeclampsia","volume":"18","author":"Vargas","year":"2011","journal-title":"Reprod. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.tice.2014.04.003","article-title":"The expression of cell cycle related proteins PCNA, Ki67, p27 and p57 in normal and preeclamptic human placentas","volume":"46","author":"Unek","year":"2014","journal-title":"Tissue Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1530\/REP-20-0638","article-title":"Appropriate expression of P57kip2 drives trophoblast fusion via cell cycle arrest","volume":"161","author":"Song","year":"2021","journal-title":"Reproduction"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.placenta.2020.11.010","article-title":"Expression of p57(KIP2) reduces growth and invasion, and induces syncytialization in a human placental choriocarcinoma cell line, BeWo","volume":"104","author":"Takahashi","year":"2021","journal-title":"Placenta"},{"key":"ref_71","first-page":"281","article-title":"p57KIP2mediated inhibition of human trophoblast apoptosis and promotion of invasion in vitro","volume":"44","author":"He","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1093\/molehr\/8.12.1129","article-title":"Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice","volume":"8","author":"Kanayama","year":"2002","journal-title":"Mol. Hum. Reprod."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"H119","DOI":"10.1152\/ajpheart.01011.2008","article-title":"Impact of diet and stress on the development of preeclampsia-like symptoms in p57kip2 mice","volume":"296","author":"Falcao","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1093\/molehr\/gal116","article-title":"Genome-wide expression profiling of placentas in the p57Kip2 model of pre-eclampsia","volume":"13","author":"Knox","year":"2007","journal-title":"Mol. Hum. Reprod."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3024","DOI":"10.1101\/gad.1718108","article-title":"Differentiation of trophoblast stem cells into giant cells is triggered by p57\/Kip2 inhibition of CDK1 activity","volume":"22","author":"Ullah","year":"2008","journal-title":"Genes Dev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/cdd.2017.172","article-title":"Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM","volume":"25","author":"Engeland","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1093\/nar\/gkv927","article-title":"The p53-p21-DREAM-CDE\/CHR pathway regulates G2\/M cell cycle genes","volume":"44","author":"Fischer","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-06364-z","article-title":"A comparative study of five physiological key parameters between four different human trophoblast-derived cell lines","volume":"7","author":"Rothbauer","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3389\/fimmu.2013.00514","article-title":"Thioredoxin\/Txnip: Redoxisome, as a redox switch for the pathogenesis of diseases","volume":"4","author":"Yoshihara","year":"2014","journal-title":"Front Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/jog.13149","article-title":"Differential expression of thioredoxin binding protein-2\/Txnip in human placenta: Possible involvement of hypoxia in its suppression during early pregnancy","volume":"43","author":"Mogami","year":"2017","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0323-2","article-title":"Oxidative stress-mediated TXNIP loss causes RPE dysfunction","volume":"51","author":"Yoon","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"4485","DOI":"10.1158\/0008-5472.CAN-04-2271","article-title":"Tumor suppressor VDUP1 increases p27(kip1) stability by inhibiting JAB1","volume":"65","author":"Jeon","year":"2005","journal-title":"Cancer Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2214\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:53:36Z","timestamp":1760165616000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2214"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,27]]},"references-count":82,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cells10092214"],"URL":"https:\/\/doi.org\/10.3390\/cells10092214","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,27]]}}}