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@ARTICLE{Woik:128557,
      author       = {N. Woik and C. T. Dietz and K. Schäker and J. Kroll$^*$},
      title        = {{K}elch-like {ECT}2-interacting protein {KLEIP} regulates
                      late-stage pulmonary maturation via {H}if-2α in mice.},
      journal      = {Disease models $\&$ mechanisms},
      volume       = {7},
      number       = {6},
      issn         = {1754-8411},
      address      = {Cambridge},
      publisher    = {Company of Biologists Limited},
      reportid     = {DKFZ-2017-04573},
      pages        = {683 - 692},
      year         = {2014},
      abstract     = {Respiratory distress syndrome (RDS) caused by preterm
                      delivery is a major clinical problem with limited
                      mechanistic insight. Late-stage embryonic lung development
                      is driven by hypoxia and the hypoxia-inducible transcription
                      factors Hif-1α and Hif-2α, which act as important
                      regulators for lung development. Expression of the BTB-and
                      kelch-domain-containing (BTB-kelch) protein KLEIP
                      (Kelch-like ECT2-interacting protein; also named Klhl20) is
                      controlled by two hypoxia response elements, and KLEIP
                      regulates stabilization and transcriptional activation of
                      Hif-2α. Based on the available data, we hypothesized an
                      essential role for KLEIP in murine lung development and
                      function. Therefore, we have performed a functional,
                      histological, mechanistic and interventional study in
                      embryonic and neonatal KLEIP(-/-) mice. Here, we show that
                      about half of the KLEIP(-/-) neonates die due to respiratory
                      failure that is caused by insufficient aeration, reduced
                      septal thinning, reduced glycogenolysis, type II pneumocyte
                      immaturity and reduced surfactant production. Expression
                      analyses in embryonic day (E) 18.5 lungs identified KLEIP in
                      lung capillaries, and showed strongly reduced mRNA and
                      protein levels for Hif-2α and VEGF; such reduced levels are
                      associated with embryonic endothelial cell apoptosis and
                      lung bleedings. Betamethasone injection in pregnant females
                      prevented respiratory failure in KLEIP(-/-) neonates,
                      normalized lung maturation, vascularization, aeration and
                      function, and increased neonatal Hif-2α expression. Thus,
                      the experimental study shows that respiratory failure in
                      KLEIP(-/-) neonates is determined by insufficient angiocrine
                      Hif-2α-VEGF signaling and that betamethasone activates this
                      newly identified signaling cascade in late-stage embryonic
                      lung development.},
      keywords     = {Basic Helix-Loop-Helix Transcription Factors (NLM
                      Chemicals) / Glucocorticoids (NLM Chemicals) / Microfilament
                      Proteins (NLM Chemicals) / endothelial PAS domain-containing
                      protein 1 (NLM Chemicals)},
      cin          = {A190},
      ddc          = {570},
      cid          = {I:(DE-He78)A190-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:24785085},
      pmc          = {pmc:PMC4036475},
      doi          = {10.1242/dmm.014266},
      url          = {https://inrepo02.dkfz.de/record/128557},
}