title: Preimplantation factor is an anti-apoptotic effector in human trophoblasts involving p53 signaling pathway.
abstract: From the earliest stages of gestation, embryonic-maternal interaction has a key role in a successful pregnancy. Various factors present during gestation may significantly influence this type of juxta/paracrine interaction. PreImplantation Factor (PIF) is a recently identified factor with activity at the fetomaternal interface. PIF is secreted by viable embryos and directly controls placental development by increasing the invasive capacity of human extravillous trophoblasts (EVTs). To further specify PIF's role in the human placenta, we analyzed the genome-wide expression profile of the EVT in the presence of a synthetic PIF analog (sPIF). We found that sPIF exposure altered several pathways related to p53 signaling, survival and the immune response. Functional assays revealed that sPIF acts through the p53 pathway to reduce both early and late trophoblast apoptosis. More precisely, sPIF (i) decreases the phosphorylation of p53 at Ser-15, (ii) enhances the B-cell lymphoma-2 (BCL2) expression and (iii) reduces the BCL2-associated X protein (BAX) and BCL2 homologous antagonist killer (BAK) mRNA expression levels. Furthermore, invalidation experiments of TP53 allowed us to demonstrate that PIF's effects on placental apoptosis seemed to be essentially mediated by this gene. We have clearly shown that p53 and sPIF pathways could interact in human trophoblast and thus promotes cell survival. Furthermore, sPIF was found to regulate a gene network related to immune tolerance in the EVT, which emphasizes the beneficial effect of this peptide on the human placenta. Finally, the PIF protein levels in placentas from pregnancies affected by preeclampsia or intra-uterine growth restriction were significantly lower than in gestational age-matched control placentas. Taken as a whole, our results suggest that sPIF protects the EVT's functional status through a variety of mechanisms. Clinical application of sPIF in the treatment of disorders of early pregnancy can be envisioned.
authors.affiliation: GIG-EA7404, Université de Versailles Saint-Quentin-en-Yvelines - Paris Saclay, Unité de Formation et de Recherche des Sciences de la Santé-Simone Veil, Montigny-le Bretonneux, France.
authors.forename: Hadia
authors.initials: H
authors.lastname: Moindjie
authors.affiliation: GIG-EA7404, Université de Versailles Saint-Quentin-en-Yvelines - Paris Saclay, Unité de Formation et de Recherche des Sciences de la Santé-Simone Veil, Montigny-le Bretonneux, France.|Service de Biologie Médicale, Centre Hospitalier de Poissy-Saint Germain, Poissy, France.
authors.forename: Esther Dos
authors.initials: ED
authors.lastname: Santos
authors.affiliation: GIG-EA7404, Université de Versailles Saint-Quentin-en-Yvelines - Paris Saclay, Unité de Formation et de Recherche des Sciences de la Santé-Simone Veil, Montigny-le Bretonneux, France.
authors.forename: Rita-Josiane
authors.initials: RJ
authors.lastname: Gouesse
authors.affiliation: Département de Biologie de la Reproduction, Cytogénétique, Gynécologie et Obstétrique, Centre Hospitalier de Poissy-Saint Germain, Poissy, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Swierkowski-Blanchard
authors.affiliation: GIG-EA7404, Université de Versailles Saint-Quentin-en-Yvelines - Paris Saclay, Unité de Formation et de Recherche des Sciences de la Santé-Simone Veil, Montigny-le Bretonneux, France.|Service de Biologie Médicale, Centre Hospitalier de Poissy-Saint Germain, Poissy, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Serazin
authors.affiliation: Society for the Investigation of Early Pregnancy, Cherry Hill, NJ, USA.|BioIncept, LLC, Cherry Hill, NJ, USA.
authors.forename: Eytan R
authors.initials: ER
authors.lastname: Barnea
authors.affiliation: GIG-EA7404, Université de Versailles Saint-Quentin-en-Yvelines - Paris Saclay, Unité de Formation et de Recherche des Sciences de la Santé-Simone Veil, Montigny-le Bretonneux, France.|Département de Biologie de la Reproduction, Cytogénétique, Gynécologie et Obstétrique, Centre Hospitalier de Poissy-Saint Germain, Poissy, France.
authors.forename: François
authors.initials: F
authors.lastname: Vialard
authors.affiliation: GIG-EA7404, Université de Versailles Saint-Quentin-en-Yvelines - Paris Saclay, Unité de Formation et de Recherche des Sciences de la Santé-Simone Veil, Montigny-le Bretonneux, France.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Dieudonné
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D010455:Peptides / Q000494:pharmacology; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011225:Pre-Eclampsia / Q000235:genetics / Q000473:pathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000378:metabolism*; D060066:Protein Interaction Maps / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014327:Trophoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D010455:Peptides; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C000605122:preimplantation factor, human; C569738:preimplantation factor, synthetic