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Role of GADD34 in age‐related differences in hyperoxiainduced stress signaling
Author(s) -
Shenberger Jeffrey,
Wu Yuchieh Melissa
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.914.9
Subject(s) - protein phosphatase 1 , signal transduction , chemistry , phosphorylation , phosphatase , medicine , endocrinology , cell , immunology , biology , biochemistry
Hyperoxic exposure activates an adaptive signal transduction pathway in the lung known as the integrated stress response (ISR), which promotes the expression of factors that modulate redox balance, the immune response, and DNA repair. Given that newborns (NB) are more tolerant to the toxic effects of O 2 than adults, we conducted the presence study to explore age‐related differences in ISR signaling within the lung. In adult (AD) mice exposed to 95% O 2 (Ox), phosphorylated eIF2α, the initiating event of the ISR, increased within 24 hrs and declined by 72 hrs coincident with enhanced GADD34, ATF3, and CHOP expression. In NB, increased p‐2α was delayed until 72 hrs and coincided with lesser increases in GADD34 and ATF3. In MEF and mouse lung epithelial cells (MLE15), Ox increased p‐2α in MLE15 but decreased p‐2α in MEF. Assessment of GADD34/PP1 phosphatase complexes revealed that the amount of PP1 precipitating with GADD34 was 3‐fold greater in MEF. Ox also decreased the association of the PP1 inhibitor I‐1 with GADD34 in both cell types, while the inhibitor BiP was present only in MLE complexes. In animals, 72 hrs of Ox increased GADD34/PP1 association by 70% and decreased I‐1/GADD34 association by 87% in AD relative to NB. These findings show that age‐related and cell specific differences in extent and duration of Ox‐induced ISR activation are likely to be mediated by the composition of GADD34/PP1 phosphatase complexes.