title: The cAMP-responsive element binding protein (CREB) transcription factor regulates furin expression during human trophoblast syncytialization.
abstract: BACKGROUND
  The multinucleated syncytiotrophoblast is formed and maintained by cytotrophoblast cell fusion and serves multiple functions to ensure a successful pregnancy. We have previously reported that the proprotein convertase furin is required for trophoblast syncytialization by processing type 1 insulin-like growth factor receptor (IGF1R).
  
  
  METHODS
  Utilizing trophoblast cell fusion models including induced fusion of choriocarcinoma BeWo cells and spontaneous fusion of primary cultured term cytotrophoblast cells, the expression of furin was evaluated by quantitative real-time PCR, Western blotting and immunofluorescence. The key transcription factor regulating the FUR gene promoter and critical responsive elements were identified by luciferase reporter assays, truncated mutants analysis, site-directed mutagenesis and ChIP.
  
  
  RESULTS
  We demonstrated that the levels of FUR mRNA were significantly stimulated by cAMP/PKA signaling pathway during spontaneous fusion of cytotrophoblast cells and forskolin-induced fusion of BeWo cells. cAMP-responsive element binding protein (CREB) was proven to be the key transcription factor which regulated the FUR P1 promoter during forskolin-induced BeWo cell fusion, and two critical cAMP-responsive elements (CREs) in the P1 promoter were further identified. Finally, we showed that CREB mediated endogenous furin activation and that CREB siRNA attenuated forskolin-induced furin expression and cell fusion in BeWo cells.
  
  
  CONCLUSIONS
  This provides the first evidence of the upstream regulator of furin during trophoblast cell fusion.
  
  
  CONCLUSIONS
  The above results suggest that the FUR transcription is activated by CREB-dependent stimulation of the FUR P1 promoter during human trophoblast syncytialization.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China; Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China; Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR China.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Human Reproductive Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100006, PR China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China; Graduate School of the Chinese Academy of Sciences, Beijing 100039, PR China.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China; Laboratory Animal Center, Chongqing Medical University, Chongqing 400016, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China. Electronic address: linhy@ioz.ac.cn.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, PR China. Electronic address: wanghm@ioz.ac.cn.
authors.forename: H
authors.initials: H
authors.lastname: Wang
mesh_terms: D002459:Cell Fusion; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D045683:Furin / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014327:Trophoblasts / Q000502:physiology*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; C468731:FURIN protein, human; D045683:Furin
keywords: CREB; Furin; Placenta; Syncytialization; Transcription promoter; Transcription regulation; Trophoblast