title: Hypoxia-induced downregulation of XIAP in trophoblasts mediates apoptosis via interaction with IMUP-2: implications for placental development during pre-eclampsia.
abstract: The regulation of trophoblast apoptosis is essential for normal placentation, and increased placental trophoblast cell apoptosis is the cause of pathologies such as intrauterine growth retardation (IUGR) and pre-eclampsia. X-linked inhibitor of apoptosis (XIAP) is expressed in trophoblasts, but little is known about the role of XIAP in placental development. In the present study, the function of XIAP in the placenta and in HTR-8/SVneo trophoblasts under hypoxic conditions was examined. In addition, the correlation between XIAP and immortalization-upregulated protein-2 (IMUP-2) was demonstrated in HTR-8/SVneo trophoblasts under hypoxia, based on a previous study showing that increased IMUP-2 induces trophoblast apoptosis and pre-eclampsia. XIAP was downregulated in pre-eclamptic placentas (P < 0.05). In HTR-8/SVneo trophoblasts, XIAP expression was decreased and the expression of apoptosis-related genes was increased in response to hypoxia. Ectopic expression of hypoxia inducible factor (HIF)-1α in HRT-8 SV/neo cells induced the nuclear translocation of XIAP and alterations of XIAP protein stability. Furthermore, hypoxia induced nuclear translocated XIAP co-localized with upregulated IMUP-2 in trophoblast nuclei, and the interaction between XIAP and IMUP-2 induced apoptosis in HRT-8 SV/neo cells. The present results suggest that hypoxia-induced down-regulation of XIAP mediates apoptosis in trophoblasts through interaction with increased IMUP-2, and that this mechanism underlies the pathogenesis of pre-eclampsia.
authors.affiliation: Department of Biomedical Science, CHA University, Seoul 135-081, Republic of Korea.
authors.forename: Su Yeon
authors.initials: SY
authors.lastname: Jeon
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kyu-Hwan
authors.initials: KH
authors.lastname: Na
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Cha
authors.forename: Jin Kyeoung
authors.initials: JK
authors.lastname: Kim
authors.forename: Jong-Wan
authors.initials: JW
authors.lastname: Park
authors.forename: Tae Ki
authors.initials: TK
authors.lastname: Yoon
authors.forename: Gi Jin
authors.initials: GJ
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D015687:Cell Hypoxia; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010929:Placentation / Q000235:genetics; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D061251:Primary Cell Culture; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C439765:C19orf33 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D010100:Oxygen