Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Degradation of proteins that are retained in the quality control apparatus of the endoplasmic reticulum (ER) has been attributed to a third proteolytic system, distinct from the lysosomal and the cytoplasmic ubiquitin-dependent proteosomal proteolytic pathways. However, several recent studies have shown that ER degradation of a mutant membrane protein, CFTRdeltaF508, is at least in part mediated from the cytoplasmic side by the 26 S proteasome. In this study, we examined the possibility that ER degradation of mutant secretory protein alpha1-antitrypsin (alpha1-AT) Z, the mutant protein associated with infantile liver disease and adult-onset emphysema of alpha1-AT deficiency, is mediated by the proteasome. The results show that a specific proteasome inhibitor, lactacystin, inhibits ER degradation of alpha1-ATZ in transfected human fibroblast cell lines and in a cell-free microsomal translocation system. Although it is relatively easy to conceptualize how a transmembrane protein like CFTRDeltaF508 might be accessible on the cytoplasmic aspect of the ER membrane for ubiquitination and degradation by the proteasome, it is more difficult to conceptualize how this might occur for a luminal polypeptide. The results show that, once within the lumen of the ER, alpha1-ATZ interacts with the transmembrane molecular chaperone calnexin and specifically induces the polyubiquitination of calnexin. The results, therefore, provide evidence that the proteasome, from its cytoplasmic localization, induces the degradation of the luminal alpha1-ATZ molecule by first attacking the cytoplasmic tail of calnexin molecules that are associated with alpha1-ATZ.
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PMID:Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. 879 55

A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes. A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases.
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PMID:Mutation of the mouse klotho gene leads to a syndrome resembling ageing. 936 84

To identify changes in gene expression associated with emphysema, differential display was used to compare RNA extracted from emphysematous lung with that of unused donor tissue taken at the time of transplant. Two expressed clones with sequence homology to the 3' UTR of the murine flotillin-1 cDNA were identified. Flotillin-1 is a plasma membrane protein, which has been associated with detergent-insoluble glycolipid-rich domains and the formation of caveolae. One clone was 95 bp longer than the other. It arose from the use of a second polyadenylation signal and its existence was not due to differential expression nor to polymorphisms in the human flotillin-1 sequence. The 1839 bp human flotillin-1 sequence was completed by 5' RACE from a lung cDNA library. The human mRNA has a 1.9 kbase transcript being highly expressed in brain, heart and lung. The single copy flotillin-1 gene is located at 6p21.3 in the MHC class I region and consists of 13 exons over 15 kb. The ORF encodes a 427 residue protein with a molecular mass 47355 Da, and an isoelectric point 7.08. Human flotillin-1 has a 98% identity with the murine protein and a 47% identity with human flotillin-2. Flotillin-1 belongs to the Band 7.2/stomatin protein family, possessing a hydrophobic N-terminal region, predicted to form a single, outside to inside, transmembrane domain. The long central alpha-helical domain may form a coiled-coil. We have isolated and characterised a cDNA encoding the human flotillin-1 gene, which may play an important role in raft formation.
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PMID:Flotillin-1: gene structure: cDNA cloning from human lung and the identification of alternative polyadenylation signals. 1116 32

Caveolin-1 (cav1) is a 22-kDa membrane protein essential to the formation of small invaginations in the plasma membrane, called caveolae. The cav1 gene is expressed primarily in adherent cells such as endothelial and smooth muscle cells and fibroblasts. Caveolae contain a variety of signaling receptors, and cav1 notably downregulates transforming growth factor (TGF)-beta signal transduction. In pulmonary pathologies such as interstitial fibrosis or emphysema, altered mechanical properties of the lungs are often associated with abnormal ECM deposition. In this study, we examined the physiological functions and the deposition of ECM in cav1(-/-) mice at various ages (1-12 mo). Cav1(-/-) mice lack caveolae and by 3 mo of age have significant reduced lung compliance and increased elastance and airway resistance. Pulmonary extravasation of fluid, as part of the cav1(-/-) mouse phenotype, probably contributed to the alteration of compliance, which was compounded by a progressive increase in deposition of collagen fibrils in airways and parenchyma. We also found that the increased elastance was caused by abundant elastic fiber deposition primarily around airways in cav1(-/-) mice at least 3 mo old. These observed changes in the ECM composition probably also contribute to the increased airway resistance. The higher deposition of collagen and elastic fibers was associated with increased tropoelastin and col1alpha2 and col3alpha1 gene expression in lung tissues, which correlated tightly with increased TGF-beta/Smad signal transduction. Our study illustrates that perturbation of cav1 function may contribute to several pulmonary pathologies as the result of the important role played by cav1, as part of the TGF-beta signaling pathway, in the regulation of the pulmonary ECM.
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PMID:The role of caveolin-1 in pulmonary matrix remodeling and mechanical properties. 1884 39

The klotho mouse shows multiple phenotypes resembling human aging caused by the mutation of a single gene. This mutation is caused by the insertion of ectopic DNA into the regulatory region of the alpha-klotho gene. The alpha-klotho gene encodes a type I membrane protein that is expressed predominantly in the kidney and brain. As a result of a defect in alpha-klotho gene expression, the klotho mouse exhibits multiple age-associated disorders, such as arteriosclerosis, osteoporosis, pulmonary emphysema and short life span. However, the mechanism by which the alpha-klotho gene product suppresses the aging phenomena has not been identified. Analysis of the pathophysiology of klotho mice is expected to give clues not only to understanding the mechanisms of individual diseases associated with aging but also the molecular mechanisms during human aging. We previously reported that the aberrant activation of mu-calpain is caused by the alpha-klotho mutation, and such change leads to degradation of cytoskeletal elements. Similar phenomena were observed in normal aged mice. Such deterioration may trigger tissue abnormalities in klotho mice and aged mice, but klotho protein may suppress these processes. We will summarize the function of alpha-klotho protein based on our research on the relationship between proteolysis and age-related disorders and the recent advanced researches.
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PMID:[Antiaging research using klotho mice]. 2004 58