EPIGALLOCATECHIN-3-GALLATE (EGCG) INHIBITS AGGREGATION OF PULMONARY FIBROSIS ASSOCIATED MUTANT SURFACTANT PROTEIN A2 THROUGH A PROTEASOME DEGRADATION PATHWAY

2018 ◽  
Vol 25 (3) ◽  
pp. 241
Author(s):  
Yongyu Wang ◽  
Lan Li ◽  
Li Dong ◽  
Xiaofang Fan ◽  
Yongsheng Gong
Keyword(s):  
Pulmonary Fibrosis ◽  
Surfactant Protein ◽  
Degradation Pathway ◽  
Proteasome Degradation

The Adaptor Molecule CIN85 Regulates Syk Tyrosine Kinase Level by Activating the Ubiquitin-Proteasome Degradation Pathway

2007 ◽  
Vol 179 (4) ◽  
pp. 2089-2096 ◽  
Author(s):  
Giovanna Peruzzi ◽  
Rosa Molfetta ◽  
Francesca Gasparrini ◽  
Laura Vian ◽  
Stefania Morrone ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Degradation Pathway ◽  
Proteasome Degradation ◽  
Adaptor Molecule ◽  
Ubiquitin Proteasome

422 URSODEOXYCHOLIC ACID MODULATES THE UBIQUITIN-PROTEASOME DEGRADATION PATHWAY OF P53

2008 ◽  
Vol 48 ◽  
pp. S162-S163
Author(s):  
J.D. Amaral ◽  
R.E. Castro ◽  
S. Sola ◽  
C.M.P. Rodrigues
Keyword(s):  
Ursodeoxycholic Acid ◽  
Degradation Pathway ◽  
Proteasome Degradation ◽  
Ubiquitin Proteasome

Increased Surfactant Protein-A Levels in Patients With Newly Diagnosed Idiopathic Pulmonary Fibrosis

CHEST Journal ◽  
2004 ◽  
Vol 125 (2) ◽  
pp. 617-625 ◽  
Author(s):  
David S. Phelps ◽  
Todd M. Umstead ◽  
Mayra Mejia ◽  
Guillermo Carrillo ◽  
Annie Pardo ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Protein A ◽  
Surfactant Protein ◽  
Surfactant Protein A ◽  
Newly Diagnosed

scholarly journals Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred

2011 ◽  
Vol 38 (4) ◽  
pp. 861-869 ◽  
Author(s):  
S. Ono ◽  
T. Tanaka ◽  
M. Ishida ◽  
A. Kinoshita ◽  
J. Fukuoka ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Protein C ◽  
Surfactant Protein ◽  
Surfactant Protein C ◽  
Familial Pulmonary Fibrosis

scholarly journals Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post-hoc analysis of the phase 3 trial in Japan

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Kimiyuki Ikeda ◽  
◽  
Hirofumi Chiba ◽  
Hirotaka Nishikiori ◽  
Arata Azuma ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Regression Analysis ◽  
Placebo Group ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Treatment Period ◽  
Surfactant Protein ◽  
Phase 3 ◽  
Post Hoc Analysis ◽  
Post Hoc

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone. Methods We conducted a post-hoc analysis of the prospective, multicenter, randomized, placebo-controlled, phase 3 trial of pirfenidone in Japan (total, n = 267; pirfenidone, n = 163; placebo, n = 104). Logistic regression analysis was performed to extract parameters that predicted disease progression, defined by a ≥ 10% relative decline in vital capacity (VC) from baseline and/or death, at week 52. For assessment of serum surfactant protein (SP)-D, SP-A and Krebs von den Lungen (KL)-6, all patients were dichotomized by the median concentration of each biomarker at baseline to the high and low biomarker subgroups. Associations of these concentrations were examined with changes in VC at each time point from baseline up to week 52, along with progression-free survival (PFS). Additionally, the effect of pirfenidone treatment on serial longitudinal concentrations of these biomarkers were evaluated. Results In the multivariate logistic regression analysis, body mass index (BMI), %VC and SP-D in the pirfenidone group, and BMI and %VC in the placebo group were indicated as predictors of disease progression. Pirfenidone treatment reduced the decline in VC with statistical significance in the low SP-D and low SP-A subgroups over most of the treatment period, and also prolonged PFS in the low SP-D and low KL-6 subgroups. Furthermore, SP-D levels over time course were reduced in the pirfenidone group from as early as week 8 until the 52-week treatment period compared with the placebo group. Conclusions Serum SP-D was the most consistent biomarker for the efficacy of pirfenidone in the cohort trial of IPF. Serial measurements of SP-D might have a potential for application as a pharmacodynamic biomarker. Trial registration The clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13, 2005 (registration No. JapicCTI-050121; http://Clinicaltrials.jp)

scholarly journals Lung Fibrosis-associated Surfactant Protein A1 and C Variants Induce Latent Transforming Growth Factor β1 Secretion in Lung Epithelial Cells

2013 ◽  
Vol 288 (38) ◽  
pp. 27159-27171 ◽  
Author(s):  
Meenakshi Maitra ◽  
Moushumi Dey ◽  
Wen-Cheng Yuan ◽  
Peter W. Nathanielsz ◽  
Christine Kim Garcia
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Surfactant Protein ◽  
Transforming Growth Factor Β1 ◽  
Lung Epithelial Cells ◽  
Missense Mutations ◽  
Lung Epithelial ◽  
Tgf Β1

Missense mutations of surfactant proteins are recognized as important causes of inherited lung fibrosis. Here, we study rare and common surfactant protein (SP)-A1 and SP-C variants, either discovered in our familial pulmonary fibrosis cohort or described by others. We show that expression of two SP-A1 (R219W and R242*) and three SP-C (I73T, M71V, and L188Q) variant proteins lead to the secretion of the profibrotic latent transforming growth factor (TGF)-β1 in lung epithelial cell lines. The secreted TGF-β1 is capable of autocrine and paracrine signaling and is dependent upon expression of the latent TGF-β1 binding proteins. The dependence upon unfolded protein response (UPR) mediators for TGF-β1 induction differs for each variant. TGF-β1 secretion induced by the expression of the common SP-A1 R219W variant is nearly completely blocked by silencing the UPR transducers IRE-1α and ATF6. In contrast, the secretion of TGF-β1 induced by two rare SP-C mutant proteins (I73T and M71V), is largely unaffected by UPR silencing or by the addition of the small molecular chaperone 4-phenylbutyric acid, implicating a UPR-independent mechanism for these variants. Blocking TGF-β1 secretion reverses cell death of RLE-6TN cells expressing these SP-A1 and SP-C variants suggesting that anti-TGF-β therapeutics may be beneficial to this molecularly defined subgroup of pulmonary fibrosis patients.

scholarly journals Molecular Mechanism of Insulin-Induced Degradation of Insulin Receptor Substrate 1

2002 ◽  
Vol 22 (4) ◽  
pp. 1016-1026 ◽  
Author(s):  
Rachel Zhande ◽  
John J. Mitchell ◽  
Jiong Wu ◽  
Xiao Jian Sun
Keyword(s):  
Insulin Receptor ◽  
Molecular Mechanism ◽  
Degradation Pathway ◽  
In Vivo Studies ◽  
Temperature Sensitive ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1 ◽  
Proteasome Degradation ◽  
Ubiquitin Proteasome

ABSTRACT Insulin receptor substrate 1 (IRS-1) plays an important role in the insulin signaling cascade. In vitro and in vivo studies from many investigators have suggested that lowering of IRS-1 cellular levels may be a mechanism of disordered insulin action (so-called insulin resistance). We previously reported that the protein levels of IRS-1 were selectively regulated by a proteasome degradation pathway in CHO/IR/IRS-1 cells and 3T3-L1 adipocytes during prolonged insulin exposure, whereas IRS-2 was unaffected. We have now studied the signaling events that are involved in activation of the IRS-1 proteasome degradation pathway. Additionally, we have addressed structural elements in IRS-1 versus IRS-2 that are required for its specific proteasome degradation. Using ts20 cells, which express a temperature-sensitive mutant of ubiquitin-activating enzyme E1, ubiquitination of IRS-1 was shown to be a prerequisite for insulin-induced IRS-1 proteasome degradation. Using IRS-1/IRS-2 chimeric proteins, the N-terminal region of IRS-1 including the PH and PTB domains was identified as essential for targeting IRS-1 to the ubiquitin-proteasome degradation pathway. Activation of phosphatidylinositol 3-kinase is necessary but not sufficient for activating and sustaining the IRS-1 ubiquitin-proteasome degradation pathway. In contrast, activation of mTOR is not required for IRS-1 degradation in CHO/IR cells. Thus, our data provide insight into the molecular mechanism of insulin-induced activation of the IRS-1 ubiquitin-proteasome degradation pathway.

Increased Expression of Proteasome-Related Genes In Patients with Primary Myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4117-4117
Author(s):  
Vibe Skov ◽  
Thomas Stauffer Larsen ◽  
Mads Thomassen ◽  
Caroline Riley ◽  
Morten Krogh Jensen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Whole Blood ◽  
Proteasome Inhibitor ◽  
Single Gene ◽  
Primary Myelofibrosis ◽  
Degradation Pathway ◽  
Gene Analysis ◽  
Proteasome Degradation ◽  
Nf Kappab

Abstract Abstract 4117 Introduction: The proteasome is an ubiquituous enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis, and angiogenesis. Since these pathways and functions are often deregulated in cancer cells, inhibition of the proteasome is an attractive potential anticancer therapy. Bortezomib (Velcade, formerly PS-341) is an extremely potent and selective proteasome inhibitor that shows strong activity against many solid and hematologic tumor types. Moreover, bortezomib, mainly by inhibition of the NF-kappaB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs. Bortezomib is a well-established treatment in multiple myeloma and studies are focusing in the potential benefit of bortezomib in other haematological malignancies, including malignant lymphomas. Since the NF-kappaB pathway is considered to be implicated in the abnormal release of cytokines in primary myelofibrosis (PMF), the proteasome inhibitor bortezomib might be a potential therapy. In a murine model, bortezomib has been demonstrated to inhibit thrombopoietin (TPO)-induced NF-kappaB activation in megakaryocytes and to reduce myeloproliferation induced by high TPO levels. Accordingly, from in vitro studies it was concluded that bortezomib might be a promising therapy for future treatment of PMF patients. Surprisingly, however, these encouraging results have not been achieved in clinical trials testing bortezomib in patients with myelofibrosis. We have performed gene expression profiling of patients with PMF and in patients with other chronic myeloproliferative neoplasms (CMPNs) in order to describe aberrant genes in the proteasome pathway in PMF. Materials and methods: The HG-U133 Plus 2.0 microarray from Affymetrix was used to profile expression of 38500 genes in whole blood from 70 patients with CMPNs, including 9 patients with PMF and 61 patients with other CMPNs. All patients were diagnosed according to the WHO criteria of a CMPN (ET=19, PV=41, PMF=9). The patients were diagnosed and followed in two institutions. Most patients were studied on cytoreductive therapy, which for the large majority included hydroxyurea. Total RNA was purified from whole blood and amplified to biotin-labeled aRNA and hybridized to microarray chips. Differences in gene expression between the two groups were calculated for each gene in the dataset by using Welch two sample t test, and the Benjamini Hochberg method was applied to control for multiple hypothesis testing (false discovery rate (FDR) < 0.05). Data were integrated with biological pathways and networks using Gene Microarray Pathway Profiler (GenMAPP 2.1) and Cytoscape 2.6.3, respectively. Hypothesis driven discovery was used to find significantly differentially expressed genes and pathways associated with PMF. Results: Single gene analysis demonstrated significantly elevated expression of seventeen proteasomal subunit genes in patients with PMF (PSMA1, PSMA2, PSMA6, PSMA7, PSMB4, PSMB5, PSMB6, PSMB7, PSMC2, PSMC3, PSMD10, PSMD14, PSMD4, PSMD8, PSMD9, PSMG1, and PSMG3 (FDR < 0.05). Only one gene, PSMB4, was significantly downregulated (FDR < 0.05). Global pathway analysis showed a significant upregulation of the proteasome degradation pathway (adjusted P < 0.03), and the network analysis revealed a significant subnetwork only composed of upregulated genes (CDC25A, CDC6, CDT1, GMNN, ORC1L, PSMA6, PSMA7, PSMB5, PSMB6, PSMB7, PSMC3, PSMD5, PSMD8, PSMD9, PSMD14) of which 10 were proteasomal genes (Z=2.6). Conclusion: In this study, we have for the first time described the gene signature of the proteasome in peripheral blood cells from patients with myelofibrosis and patients with ET and PV. Using single gene analysis, global pathway and network analysis, we found significant upregulation of the proteasomal transcriptome in patients with PMF as compared to patients with ET and PV as a group. This study has added new important information of the genes involved in the upregulation of the proteasome degradation pathway in these patients. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document