Functional Genomic Responses to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and CFTRΔ508 in the Lung

Abstract

Cystic fibrosis (CF), a common lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that disturbs fluid homeostasis and host defense in target organs. The effects of CFTR and ⌬508-CFTR were assessed in transgenic mice that 1) lack CFTR expression (Cftr induced genes encoding heat shock proteins and other chaperones but did not activate the endoplasmic reticulum-associated degradation pathway. RNAs encoding proteins that directly interact with CFTR were identified in each of the CFTR mouse models, supporting the hypothesis that CFTR functions within a multiprotein complex whose members interact at the level of protein-protein interactions and gene expression. Promoters of genes influenced by CFTR shared common regulatory elements, suggesting that their co-expression may be mediated by shared regulatory mechanisms. Genes and pathways involved in the response to CFTR may be of interest as modifiers of CF.

De Novo Biosynthetic Profiling of High Abundance Proteins in Cystic Fibrosis Lung Epithelial Cells

“…An overlap with human CF cells would be unexpected and was not found. A recent study has also been reported that was limited to genomic changes in whole mouse lung tissue in response to either wild type or mutant human CFTR (22). Again no parallels occurred with the proteomic changes reported here in human lung CF epithelial cells.…”

SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production

“…Affymetrix Microarray Suite 5.0 was used to scan and quantitate the gene chips under default scan settings. Hybridization data were subjected sequentially to normalization, transformation, filtration, and functional classification and pathway analysis as previously described (50,51). Data analysis was performed with BRB Array Tools software package (http://linus.nci.nih.gov/BRB-ArrayTools.html).…”

Inhibition of acinar apoptosis occurs during acute pancreatitis in the human homologue ΔF508 cystic fibrosis mouse

“…For example, studies of genomic responses indicate that mouse respiratory epithelial cells from both CF models had similar constitutive overexpression of genes influencing several regulatory processes (81,82), but ⌬F508-CF mice had "a primary disturbance in expression of genes regulating redox and antioxidant systems" (82). Hence, comparisons between ⌬F508-CF and UNC-CF mouse pancreas phenotypes may provide insight into CFTR genotype-phenotype correlations and illustrate how seemingly minor differences in exon 10 mutations of the CFTR gene may exert individual effects on cellular processes.…”