Zfp148 Deficiency Causes Lung Maturation Defects and Lethality in Newborn Mice That Are Rescued by Deletion of p53 or Antioxidant Treatment

• 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

Animals

Animals

Newborn

Antioxidants

pharmacology

Apoptosis

Blotting

Southern

Blotting

Western

Cell Cycle

Cell Proliferation

Cells

Cultured

DNA-Binding Proteins

physiology

Embryo

Mammalian

cytology

drug effects

metabolism

Female

Fibroblasts

cytology

drug effects

metabolism

Gene Deletion

Genes

Lethal

Immunoenzyme Techniques

Lung

drug effects

embryology

metabolism

Mice

Mice

Inbred C57BL

Mice

Knockout

Oxidative Stress

drug effects

RNA

Messenger

genetics

Real-Time Polymerase Chain Reaction

Respiratory Tract Diseases

genetics

pathology

prevention & control

Reverse Transcriptase Polymerase Chain Reaction

Transcription Factors

physiology

Tumor Suppressor Protein p53

deficiency

genetics

Publication and Content Type

ref (subject category)

art (subject category)