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Li C.,Los Angeles CountyUniversity of Southern California Medical Center | Bellusci S.,Excellence Cluster Cardio Pulmonary System ECCPS | Bellusci S.,Universities of Giessen and Marburg Lung Center | Bellusci S.,Saban Research Institute | And 2 more authors.
Journal of Biochemistry

The role of WNT signalling in metazoan organogenesis has been a topic of widespread interest. In the lung, while the role of canonical WNT signalling has been examined in some detail by multiple studies, the non-canonical WNT signalling has received limited attention. Reliable evidence shows that this important signalling mechanism constitutes a major regulatory pathway in lung development. In addition, accumulating evidence has also shown that the non-canonical WNT pathway is critical for maintaining lung homeostasis and that aberrant activation of this pathway may underlie several debilitating lung diseases. Functional analyses have further revealed that the non-canonical WNT pathway regulates multiple cellular activities in the lung that are dependent on the specific cellular context. In most cell types, non-canonical WNT signalling regulates canonical WNT activity, which is also critical for many aspects of lung biology. This review will summarize what is currently known about the role of non-canonical WNT signalling in lung development, homeostasis and pathogenesis of disease. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved. Source

Shi J.,U.S. National Cancer Institute | Marconett C.N.,University of Southern California | Duan J.,University of Illinois at Chicago | Hyland P.L.,U.S. National Cancer Institute | And 28 more authors.
Nature communications

The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF-binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, four of the five established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome. Source

Kage H.,Will Rogers Institute Pulmonary Research Center | Flodby P.,Will Rogers Institute Pulmonary Research Center | Gao D.,Will Rogers Institute Pulmonary Research Center | Kim Y.H.,Will Rogers Institute Pulmonary Research Center | And 8 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology

Claudins are tight junction proteins that regulate paracellular ion permeability of epithelium and endothelium. Claudin 4 has been reported to function as a paracellular sodium barrier and is one of three major claudins expressed in lung alveolar epithelial cells (AEC). To directly assess the role of claudin 4 in regulation of alveolar epithelial barrier function and fluid homeostasis in vivo, we generated claudin 4 knockout (Cldn4 KO) mice. Unexpectedly, Cldn4 KO mice exhibited normal physiological phenotype although increased permeability to 5-carboxyfluorescein and decreased alveolar fluid clearance were noted. Cldn4 KO AEC monolayers exhibited unchanged ion permeability, higher solute permeability, and lower short-circuit current compared with monolayers from wild-type mice. Claudin 3 and 18 expression was similar between wild-type and Cldn4 KO alveolar epithelial type II cells. In response to either ventilator-induced lung injury or hyperoxia, claudin 4 expression was markedly upregulated in wild-type mice, whereas Cldn4 KO mice showed greater degrees of lung injury. RNA sequencing, in conjunction with differential expression and upstream analysis after ventilator-induced lung injury, suggested Egr1, Tnf, and Il1b as potential mediators of increased lung injury in Cldn4 KO mice. These results demonstrate that claudin 4 has little effect on normal lung physiology but may function to protect against acute lung injury. © 2014 the American Physiological Society. Source

Pfaffenbach K.T.,University of Southern California | Pong M.,University of Southern California | Morgan T.E.,University of Southern California | Wang H.,Will Rogers Institute Pulmonary Research Center | And 4 more authors.
Journal of Cellular Physiology

Glucose regulated protein 78/immunoglobulin binding protein (GRP78/BiP) is an endoplasmic reticulum (ER) chaperone protein and master regulator of the unfolded protein response (UPR). The response of GRP78 to overt pharmacologically induced ER stress is well established, whereas the modulation of GRP78 to physiologic changes is less characterized. In this study, we examined the regulation of GRP78 in response to reduced IGF-1 growth factor signaling, a common consequence of calorie restriction (CR). ER chaperone protein expression was quantified in cell lysates prepared from the livers of calorie restricted (CR) and ad libitum fed mice, as well as MEFs grown in normal medium or serum starved. The requirement of IGF-1 signaling on GRP78 expression was studied using MEFs with IGF-1 receptor overexpression (R+) or deletion (R-), and the regulatory mechanism was examined using mTORC1 and PI3K inhibitors, as well as R- cells with knockdown of transcription factor FOXO1 compared to shRNA control. We observed a 40% reduction in GRP78 protein expression in CR mice and in serum-starved MEF cells. R- cells had drastically reduced AKT phosphorylation and exhibited lower levels of ER chaperones, in particular 80% less GRP78. Despite an 80% reduction in GRP78 expression, R- cells were not under chronic ER stress, but were fully capable of activating the UPR. Neither forced expression of FOXO1-AAA nor knockdown of FOXO1 in R- cells affected GRP78 expression. In conclusion, we report that IGF-1 receptor signaling regulates GRP78 expression via the PI3K/AKT/mTORC1 axis independent of the canonical UPR and FOXO1. © 2012 Wiley Periodicals, Inc. Source

Flodby P.,Will Rogers Institute Pulmonary Research Center | Borok Z.,Will Rogers Institute Pulmonary Research Center | Banfalvi A.,Will Rogers Institute Pulmonary Research Center | Zhou B.,Will Rogers Institute Pulmonary Research Center | And 5 more authors.
American Journal of Respiratory Cell and Molecular Biology

Pulmonary alveolar epithelium is comprised of two morphologically and functionally distinct cell types, alveolar epithelial type (AT) I and AT2 cells. Genetically modified mice with cell-specific Cre/loxP-mediated knockouts of relevant genes in each respective cell type would be useful to help elucidate the relative contributions of AT1 versus AT2 cells to alveolar homeostasis. Cre has previously been efficiently expressed in AT2 cells in mouse lung with the surfactant protein (SP)-C promoter; however, no transgenic mouse expressing Cre in AT1 cells has so far been available. To develop an AT1 cell-specific transgenic Cre mouse, we generated a knockin of a Cre-IRES-DsRed cassette into exon 1 of the endogenous aquaporin 5 (Aqp5) gene, a gene expressed specifically in AT1 cells in the distal lung epithelium, resulting in the mouse line, Aqp5-Cre-IRES-DsRed (ACID). Endogenous Aqp5 and transgenic Cre in ACID mice showed a very similar pattern of tissue distribution by RT-PCR. To analyze Cre activity, ACID was crossed to two Cre reporter strains, R26LacZ and mT/mG. Double-transgenic offspring demonstrated reporter gene expression in a very high fraction of AT1 cells in the distal lung, whereas AT2 cells were negative. As expected, variable reporter expression was detected in several other tissues where endogenous Aqp5 is expressed (e.g., submandibular salivary gland and stomach). ACID mice should be of major utility in analyzing the functional contribution of AT1 cells to alveolar epithelial properties in vivo with Cre/loxP-mediated gene deletion technology. Source

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