The Wnt/␤-catenin signaling cascade activates genes that allow cells to adopt particular identities throughout development. In adult self-renewing tissues like intestine and blood, activation of the Wnt pathway maintains a progenitor phenotype, whereas forced inhibition of this pathway promotes differentiation. In the lung alveolus, type 2 epithelial cells (AT2) have been described as progenitors for the type 1 cell (AT1), but whether AT2 progenitors use the same signaling mechanisms to control differentiation as rapidly renewing tissues is not known. We show that adult AT2 cells do not exhibit constitutive ␤-catenin signaling in vivo, using the AXIN2

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Asbestos exposure results in pulmonary fibrosis (asbestosis) and malignancies (bronchogenic lung cancer and mesothelioma) by mechanisms that are not fully understood. Alveolar epithelial cell (AEC) apoptosis is important in the development of pulmonary fibrosis after exposure to an array of toxins, including asbestos. An endoplasmic reticulum (ER) stress response and mitochondriaregulated (intrinsic) apoptosis occur in AECs of patients with idiopathic pulmonary fibrosis, a disease with similarities to asbestosis. Asbestos induces AEC intrinsic apoptosis, but the role of the ER is unclear. The objective of this study was to determine whether asbestos causes an AEC ER stress response that promotes apoptosis. Using human A549 and rat primary isolated alveolar type II cells, amosite asbestos fibers increased AEC mRNA and protein expression of ER stress proteins involved in the unfolded protein response, such as inositol-requiring kinase (IRE) 1 and X-box-binding protein- Asbestos fibers are a naturally occurring group of mineral silicates (amphiboles and chrysotile) in which environmental and occupational exposure causes pulmonary and pleural fibrosis, lung cancer, and mesothelioma by mechanisms that are not fully established (see Refs. 1-3 for review). Alveolar epithelial cell (AEC) apoptosis is one important early event implicated in the pathogenesis of pulmonary fibrosis after exposure to various toxins, including asbestos (3, 4). Asbestos fibers are internalized by AECs soon after exposure, resulting in the production of iron-derived reactive oxygen species (ROS), DNA damage, and apoptosis (1-3). The mitochondria (intrinsic) apoptotic death pathway is mediated by proapoptotic Bcl-2 family members (e.g., Bax, Bak, and others) after activation by diverse stimuli, such as ROS, DNA damage, ceramide, and calcium, while antiapoptotic Bcl-2 family members (e.g., Bcl-2, Bcl-X L , etc.) are protective (5, 6). Apoptotic stimuli subsequently result in permeabilization of the outer mitochondrial membrane, reductions in mitochondrial membrane potential and apoptosome formation that activates caspase-9 and downstream caspase-3. We previously showed that ironderived ROS from the mitochondria mediate asbestos-induced AEC DNA damage and apoptosis via the mitochondria-regulated death pathway, and that overexpression of Bcl-X L is protective (7,8). Endoplasmic reticulum (ER) stress can also lead to intrinsic apoptosis, but its role after asbestos exposure has not been studied. The ER is responsible for both intracellular Ca 21 storage and for the folding, maturation, and transport of nascent proteins. Conditions that disrupt these processes, including oxidative stress, perturbation of Ca 21 , and/or accumulation of unfolded and/or misfolded proteins, result in ER stress (see Refs. 3, 4, 6 for review).Accumulating evidence convincingly show that ER stress occurs in AECs undergoing apoptosis in patients with idiopathic pulmonary fibrosis (IPF), and may contribute to epithelialmesenchymal transition, but the pathophysiologic signific...

Background: β-catenin is a dual function adhesion/transcriptional co-activator protein, and both functions are critical for normal tissue homeostasis. Since the transcriptional functions of β-catenin are more often implicated in various disease processes, there is much interest in the development and use of reagents to interrogate spatial and temporal evidence of β-catenin nuclear signaling in cells and tissues. An important study demonstrated that the signaling form of β-catenin is specifically unphosphorylated at residues S37 and T41, and suggested that this form exhibits a propensity for cytosolic/nuclear accumulation relative to the total pool of β-catenin.