title: Zfp148 deficiency causes lung maturation defects and lethality in newborn mice that are rescued by deletion of p53 or antioxidant treatment.
abstract: The transcription factor Zfp148 (Zbp-89, BFCOL, BERF1, htβ) interacts physically with the tumor suppressor p53 and is implicated in cell cycle control, but the physiological role of Zfp148 remains unknown. Here we show that Zfp148 deficiency leads to respiratory distress and lethality in newborn mice. Zfp148 deficiency prevented structural maturation of the prenatal lung without affecting type II cell differentiation or surfactant production. BrdU analyses revealed that Zfp148 deficiency caused proliferation arrest of pulmonary cells at E18.5-19.5. Similarly, Zfp148-deficient fibroblasts exhibited proliferative arrest that was dependent on p53, raising the possibility that cell stress is part of the underlying mechanism. Indeed, Zfp148 deficiency lowered the threshold for activation of p53 under oxidative conditions. Moreover, both in vivo and cellular phenotypes were rescued on Trp53(+/-) or Trp53(-/-) backgrounds and by antioxidant treatment. Thus, Zfp148 prevents respiratory distress and lethality in newborn mice by attenuating oxidative stress-dependent p53-activity during the saccular stage of lung development. Our results establish Zfp148 as a novel player in mammalian lung maturation and demonstrate that Zfp148 is critical for cell cycle progression in vivo.
authors: Wallenberg Laboratory, Institute of Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors: Volkan I
authors: VI
authors: Sayin
authors: Anna
authors: A
authors: Nilton
authors: Mohamed X
authors: MX
authors: Ibrahim
authors: Pia
authors: P
authors: Ågren
authors: Erik
authors: E
authors: Larsson
authors: Marleen M
authors: MM
authors: Petit
authors: Lillemor Mattsson
authors: LM
authors: Hultén
authors: Marcus
authors: M
authors: Ståhlman
authors: Bengt R
authors: BR
authors: Johansson
authors: Martin O
authors: MO
authors: Bergo
authors: Per
authors: P
authors: Lindahl
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D005804:Genes, Lethal; D007124:Immunoenzyme Techniques; D008168:Lung / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012140:Respiratory Tract Diseases / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C491741:Zfp148 protein, mouse