b Nrf2 (nuclear factor erythroid 2-related factor 2) is an antioxidant transcription factor. AMP-activated protein kinase (AMPK) functions as a central regulator of cell survival in response to stressful stimuli. Nrf2 should be coordinated with the cell survival pathway controlled by AMPK, but so far the mechanistic connections remain undefined. This study investigated the role of AMPK in Nrf2 trafficking and its activity regulation. A subnetwork integrating neighbor molecules suggested direct interaction between AMPK and Nrf2. In cells, AMPK activation caused nuclear accumulation of Nrf2. In the in vitro kinase and peptide competition assays, AMPK phosphorylated Nrf2 at the Ser558 residue (Ser550 in mouse) located in the canonical nuclear export signal. Nrf2 with an S550A mutation failed to be accumulated in the nucleus after AMPK activation. Leptomycin B, a nuclear export inhibitor, did not enhance nuclear accumulation of wild-type Nrf2 (WT-Nrf2) activated by AMPK or a phospho-Ser550-mimetic Nrf2 mutant, corroborating the finding that AMPK facilitated nuclear accumulation of Nrf2, probably by inhibiting nuclear export. Activated glycogen synthase kinase 3 (GSK3) diminished the basal nuclear level of Myc-S550A-Nrf2. Taking the data collectively, AMPK phosphorylates Nrf2 at the Ser550 residue, which, in conjunction with AMPK-mediated GSK3 inhibition, promotes nuclear accumulation of Nrf2 for antioxidant response element (ARE)-driven gene transactivation. Redox homeostasis in the cell may be disturbed by a deficiency in energy production as well as by reactive oxygen species (ROS) generated from xenobiotic biotransformation or the process of fuel oxidation (1-3). Nrf2 (nuclear factor erythroid 2-related factor 2), a key antioxidant transcription factor, participates in maintaining redox homeostasis in the cell (4). Various physiological or pathological circumstances accompanying free radical generation activate Nrf2 as a consequence of an adaptive response to oxidative stress (5). However, the regulation of Nrf2 has been minimally studied in the context of cellular energy deficiency (e.g., starvation, hypoxia, and exercise).The response of Nrf2 to oxidative challenge stress rapidly occurs mainly through phosphorylation at Ser40; protein kinase C␦ (PKC␦) induces activation of phosphorylation of Nrf2 at the residue, and the phosphorylated form is then released from Keap-1 and is stabilized for antioxidant response element (ARE)-driven gene expression (6, 7). An active form of Nrf2 has been shown to localize in the nucleus and binds to the ARE(s) present in the promoter regions of target genes (8). In this process, phosphoinositide 3-kinase controls nuclear translocation of Nrf2 (9). In contrast, glycogen synthase kinase 3 (GSK3) catalyzes the inhibitory phosphorylation of Nrf2 for the tight activity control (10, 11). Other kinases, including mitogen-activated protein kinases and Fyn, may also affect Nrf2 activity (12, 13). Despite the identification of oxidative stress-associated Nrf2 kinases, the characterist...
The histopathologic pattern provides the most important prognostic marker for idiopathic interstitial pneumonia; however, studies have suggested that short-term changes in lung function may be more important. We investigated the prognostic factors for fibrotic interstitial pneumonia. The clinical features and follow-up course of 179 patients (131 with idiopathic pulmonary fibrosis and 48 with nonspecific interstitial pneumonia; 41 fibrotic types and 7 cellular) were analyzed retrospectively. The lung function indices improved or stabilized in most patients with fibrotic nonspecific interstitial pneumonia in contrast to the deterioration or stable condition of most patients with idiopathic pulmonary fibrosis. The 5-year survival of patients with fibrotic nonspecific interstitial pneumonia (76.2%) was better than for those with idiopathic pulmonary fibrosis (43.8%) (p = 0.007). Multivariate analysis at the time of presentation revealed that pathologic pattern, age, and diffusion capacity had important prognostic implications. However, after 6 months of follow-up, changes in FVC, initial diffusion capacity, and sex were the only independent prognostic factors, with no additional prognostic information conferred by the histologic diagnosis. Our data confirmed the importance of physiological parameters including short-term change in FVC. However, at the time of diagnosis, histopathology was important for the prediction of prognosis and future change in lung function.
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