Genes related to emphysema are enriched for ubiquitination pathways

BMC Pulmonary Medicine

Ma’en Obeidat²  Peter D Paré²  Melody Morris³  Michael Crackower³  Gary O’Neill³  Don D Sin²  James C Hogg²  Christopher J Roberts³  Silvija Coulter³  Leanna Loy²  Jerry Wong²  Honglin Luo²  Shizu Hayashi²  Mark Elliott²  Brian Kennedy³  James Mortimer³  Yves Boie³  I-Ming Wang³  Sergey Stepaniants¹ 

[1] Covance Genomics Laboratory, Indianapolis, USA;University of British Columbia Centre for Heart and Lung Innovation, St Paul’s Hospital, 1081 Burrard St, Vancouver V6Z 1Y6, BC, Canada;Merck Research Laboratory, Rahway, USA

关键词: Protein ubquitination;    Cigarette smoking;    mRNA;    Transcriptional analysis;    Gene expression;    Surface area to lung volume ratio;    Pulmonary emphysema;   

Others  :  1091163
DOI  :  10.1186/1471-2466-14-187

 received in 2014-04-05, accepted in 2014-11-19,  发布年份 2014

【 摘 要 】

Background

Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD). The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration. Despite their convergence in altered physiology, different mechanisms contribute to these processes. The relationships between gene expression and these specific phenotypes may be more revealing than comparison with lung function.

Methods

We measured the ratio of alveolar surface area to lung volume (SA/V) in lung tissue from 43 smokers. Two samples from 21 subjects, in which SA/V differed by >49 cm²/mL were profiled to select genes whose expression correlated with SA/V. Significant genes were tested for replication in the 22 remaining subjects.

Results

The level of expression of 181 transcripts was related to SA/V ( p < 0.05). When these genes were tested in the 22 remaining subjects as a replication, thirty of the 181 genes remained significantly associated with SA/V (P < 0.05) and the direction of association was the same in 164/181. Pathway and network analysis revealed enrichment of genes involved in protein ubiquitination, and western blotting showed altered expression of genes involved in protein ubiquitination in obstructed individuals.

Conclusion

This study implicates modified protein ubiquitination and degradation as a potentially important pathway in the pathogenesis of emphysema.

【 授权许可】

   
2014 Stepaniants et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 1.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Barnes PJ: New concepts in chronic obstructive pulmonary disease. Annu Rev Med 2003, 54(1):113-129.
• [2]Coxson HO, Rogers RM, Whittall KP, D'Yachkova Y, Paré PD, Sciurba FC, Hogg JC: A quantification of the lung surface area in emphysema using computed tomography. Am J Respir Crit Care Med 1999, 159(3):851-856.
• [3]Wang IM, Stepaniants S, Boie Y, Mortimer JR, Kennedy B, Elliott M, Hayashi S, Loy L, Coulter S, Cervino S, Harris J, Thornton M, Raubertas R, Roberts C, Hogg JC, Crackower M, O'Neill G, Paré PD: Gene expression profiling in patients with chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med 2008, 177(4):402-411.
• [4]Retamales I, Elliott WM, Meshi B, Coxson HO, Paré PD, Sciurba FC, Rogers RM, Hayashi S, Hogg JC: Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001, 164(3):469-473.
• [5]Bhattacharya S, Srisuma S, Demeo DL, Shapiro SD, Bueno R, Silverman EK, Reilly JJ, Mariani TJ: Molecular biomarkers for quantitative and discrete COPD phenotypes. Am J Respir Cell Mol Biol 2009, 40(3):359-367.
• [6]Ning W, Li C-J, Kaminski N, Feghali-Bostwick CA, Alber SM, Di YP, Otterbein SL, Song R, Hayashi S, Zhou Z, Pinsky DJ, Watkins SC, Pilewski JM, Sciurba FC, Peters DG, Hogg JC, Choi AMK: Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A 2004, 101(41):14895-14900.
• [7]Spira A, Beane J, Pinto-Plata V, Kadar A, Liu G, Shah V, Celli B, Brody JS: Gene expression profiling of human lung tissue from smokers with severe emphysema. Am J Respir Cell Mol Biol 2004, 31(6):601-610.
• [8]Patel BD, Coxson HO, Pillai SG, Agustí AGN, Calverley PMA, Donner CF, Make BJ, Müller NL, Rennard SI, Vestbo J, Wouters EFM, Hiorns MP, Nakano Y, Camp PG, Nasute Fauerbach PV, Screaton NJ, Campbell EJ, Anderson WH, Paré PD, Levy RD, Lake SL, Silverman EK, Lomas DA: Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008, 178(5):500-505.
• [9]McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, Wright AC, Gefter WB, Litzky L, Coxson HO, Paré PD, Sin DD, Pierce RA, Woods JC, McWilliams AM, Mayo JR, Lam SC, Cooper JD, Hogg JC: Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011, 365(17):1567-1575.
• [10]Campbell J, McDonough J, Zeskind J, Hackett T, Pechkovsky D, Brandsma C-A, Suzuki M, Gosselink J, Liu G, Alekseyev Y, Xiao J, Zhang X, Hayashi S, Cooper J, Timens W, Postma D, Knight D, Marc L, James H, Avrum S: A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. Genome Med 2012, 4(8):67.
• [11]Hartl FU, Bracher A, Hayer-Hartl M: Molecular chaperones in protein folding and proteostasis. Nature 2011, 475(7356):324-332.
• [12]Mu T-W, Ong DST, Wang Y-J, Balch WE, Yates JR, Segatori L, Kelly JW: Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 2008, 134(5):769-781.
• [13]Min T, Bodas M, Mazur S, Vij N: Critical role of proteostasis-imbalance in pathogenesis of COPD and severe emphysema. J Mol Med 2011, 89(6):577-593.
• [14]Cantin AM, Richter MV: Cigarette smoke-induced proteostasis imbalance in obstructive lung diseases. Curr Mol Med 2012, 12(7):836-849.
• [15]Bodas M, Tran I, Vij N: Therapeutic strategies to correct proteostasis-imbalance in chronic obstructive lung diseases. Curr Mol Med 2012, 12(7):807-814.
• [16]Meiners S, Eickelberg O: What shall we do with the damaged proteins in lung disease? ask the proteasome! Eur Respir J 2012, 40(5):1260-1268.
• [17]Hegde AN, Upadhya SC: Role of ubiquitin-proteasome-mediated proteolysis in nervous system disease. Biochim Biophys Acta 2011, 1809(2):128-140.
• [18]Luo H, Wong J, Wong B: Protein degradation systems in viral myocarditis leading to dilated cardiomyopathy. Cardiovasc Res 2010, 85(2):347-356.
• [19]Somborac-Bacura A, van der Toorn M, Franciosi L, Slebos DJ, Zanic-Grubisic T, Bischoff R, van Oosterhout AJ: Cigarette smoke induces endoplasmic reticulum stress response and proteasomal dysfunction in human alveolar epithelial cells. Exp Physiol 2013, 98(1):316-325.
• [20]van Rijt SH, Keller IE, John G, Kohse K, Yildirim AO, Eickelberg O, Meiners S: Acute cigarette smoke exposure impairs proteasome function in the lung. Am J Physiol Lung Cell Mol Physiol 2012, 303(9):L814-823.
• [21]Ciechanover A: The ubiquitin-proteasome pathway: on protein death and cell life. Embo J 1998, 17(24):7151-7160.
• [22]Glickman MH, Ciechanover A: The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002, 82(2):373-428.
• [23]Myung J, Kim KB, Crews CM: The ubiquitin-proteasome pathway and proteasome inhibitors. Med Res Rev 2001, 21(4):245-273.
• [24]Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW: Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev 2004, 18(21):2573-2580.
• [25]Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Doi S, Fujita K, Miyatake A, Enomoto T, Miyagawa T, Adachi M, Tanaka H, Niimi A, Matsumoto H, Ito I, Masuko H, Sakamoto T, Hizawa N, Taniguchi M, Lima JJ, Irvin CG, Peters SP, Himes BE, Litonjua AA, Tantisira KG, Weiss ST, Kamatani N, Nakamura Y, Tamari M: Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet 2011, 43(9):893-896.
• [26]Kimura Y, Tanaka K: Regulatory mechanisms involved in the control of ubiquitin homeostasis. J Biochem 2010, 147(6):793-798.
• [27]Tursun B, Schluter A, Peters MA, Viehweger B, Ostendorff HP, Soosairajah J, Drung A, Bossenz M, Johnsen SA, Schweizer M, Bernard O, Bach I: The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones. Genes Dev 2005, 19(19):2307-2319.
• [28]Gorovoy M, Han J, Pan H, Welch E, Neamu R, Jia Z, Predescu D, Vogel S, Minshall RD, Ye RD, Malik AB, Voyno-Yasenetskaya T: LIM kinase 1 promotes endothelial barrier disruption and neutrophil infiltration in mouse lungs. Circ Res 2009, 105(6):549-556.