br Protein protein interactions of LEI
Protein-protein interactions of LEI/L-DNase II and the control of cell death
Evolutionary tips The serpin inhibitory mechanism is extremely well adapted to evolutionary changes because a single amino CGP41251 substitution in the RSL can led to the inhibition of a totally different protease. We have just seen the surprising capacity of SERPINB1 to become an endonuclease but other serpins have developed analogous properties, related to DNA status. For example, α1-antichymotrypsin (inhibitor of cathepsin G and chymase), is able to inhibit purified DNA polymerase and DNA primase . MENT (Myeloid and Erythroid Nuclear Termination stage-specific protein), is an inhibitor of cathepsins K, L, and V, as well as a cysteine proteinase from CV-1 cells . It is a nuclear protein present in the avian blood cells where it is the predominant non-histone protein. MENT imposes a dramatic remodeling of chromatin by forming “bridges” between nucleosomes, bringing about a strong repressive effect on cell proliferation.
Other functions of SERPINB1 On one hand, we have recently shown that in bovine corneal epithelium LEI increases its expression early after injury and returns to basal levels immediately after wound closure . This increase is blocked by N-acetylcysteine, suggesting that production of reactive oxygen species immediately after wounding is involved in this overexpression. On the other hand, SERPINB1 expression was shown to be down-regulated in high-grade human glioma and glioblastoma cell lines. Overexpression of SERPINB1 suppressed, while knock-down of SERPINB1 promoted, the migration and invasion of glioma cells. Further studies conducted on glioma cells indicate that SERPINB1 inhibited glioma migration and invasion by dampening the expression of matrix metalloproteinase-2 (MMP-2) and by inactivating focal adhesion kinase (FAK) phosphorylation, which is involved in the down regulation of MMP-2 . Moreover, in human keratinocyte cell line (HaCaT) proliferation was decreased by treatment with calcitriol which is mediated by an up regulation of SERPINB1 . Other studies suggested that SERPINB1 may suppress the migration and invasion of lung and breast cancers as well as hepatocellular carcinoma cells. However, the differential proteomes of two oral cancer cells, CAL-27 and SAS, with the highest and the lowest migration potential, respectively, show that SERPINB1 was highly expressed in CAL-27 . In this case expression of SERPINB1 correlated positively with cell migration. This was supported by the ectopic expression of SERPINB1 in oral cancer cells, in which the overexpression of the protein increased cell migration.
Introduction Chronic Obstructive Pulmonary Disease (COPD) is one of the leading causes responsible for worldwide mortality and morbidity. Owing to its rising prevalence, the management of the disease has become a formidable challenge for the present healthcare systems. Currently, COPD has around 11.7% global prevalence and is the fourth leading cause of worldwide deaths , , . Further, with the rise in ratio of smokers, aging population in developed nations, prevalence of obesity, and outdoors pollution, projections are that the disease will be the third leading cause of worldwide deaths by 2020 , , , , . Surprisingly, the available therapies against the disease have limited efficacy , , , . Furthermore, lesser effectiveness of steroids in managing COPD associated inflammation makes it imperative to better understand the disease pathogenesis and find new therapeutic targets , , . PARPs comprise 18-membered family of proteins that carry out post-translational modifications of the target proteins by transfer of mono/poly ADP-ribose moieties, using NAD+ as a substrate . Among the different members of family, PARP-1 is the most important and extensively studied member. It is responsible for the majority (85–90%) of poly(ADP-ribosyl)ation in cell , . Originally, it was assumed that the protein is primarily involved in dealing with cellular stresses and plays an active role in DNA repair but in recent past pro-inflammatory role of this protein has emerged. It is now known that the over activation of PARP-1 (under severe/persistent DNA damage conditions) leads to depletion of its substrate .i.e. NAD+ and thus causes necrosis . Additionally, there are growing numbers of reports showing that PARP-1 regulates the expression of several NF-κB dependent cytokines, chemokines, adhesion molecules, inducible nitric-oxide synthase (iNOS), which play a critical role in manifestation of inflammatory cycle , , , , . Since cigarette smoke, chronic inflammation, oxidative stress, nitrosative stress are associated with COPD pathogenesis, the reactive oxygen species (ROS) induced-DNA damage is also increased in patients with COPD , , . Thus, persistent activation of PARP-1 during the disease progression has been reported , . Interestingly, several studies have reported key role of PARP-1 in asthma and acute lung injury pathogenesis , , , , . In addition, pro-inflammatory role of the protein has been reported in bleomycin-induced lung fibrosis . However, only few studies have been conducted evaluating the roles of PARP-1 in COPD and research has been limited primarily to patients’ blood samples , , . The present study was designed with an aim to decipher role of PARP-1 in COPD pathogenesis using elastase-induced mouse model of the disease. Olaparib (Lynparza/AZD2281), a new generation competitive PARP inhibitor approved by US food and drug administration (FDA) and the European medicines agency (EMA) in ovarian cancer patients, was used in this study, and effects of PARP-1 inhibition on elastase-induced inflammation and emphysema were analyzed.