| 1 | Proteomic Analysis Shows Constitutive Secretion of MIF and p53-associated Activity of COX-2-/-Lung Fibroblasts显示文摘The differential expression of two closelyassociated cyclooxygenase isozymes, COX-1 and COX-2, exhibited functions beyond eicosanoid metabolism. We hypothesized that COX-1 or COX-2 knockout lung ?broblasts may display altered protein pro?les which may allow us to further differentiate the functional roles of these isozymes at the molecular level. Proteomic analysis shows constitutive production of macrophage migration inhibitory factor(MIF) in lung ?broblasts derived from COX-2^(-/-)but not wild-type(WT) or COX-1à/àmice. MIF was spontaneously released in high levels into the extracellular milieu of COX2^(-/-) ?broblasts seemingly from the preformed intracellular stores, with no change in the basal gene expression of MIF. The secretion and regulation of MIF in COX-2^(-/-)was ‘‘prostaglandin-independent.' GO analysis showed thatconcurrent with upregulation of MIF, there is a signi?cant surge in expression of genes related to?broblast growth, FK506 binding proteins, and isomerase activity in COX-2^(-/-)cells. Furthermore,COX-2^(-/-)?broblasts also exhibit a signi?cant increase in transcriptional activity of various regulators, antagonists, and co-modulators of p53, as well as in the expression of oncogenes and related transcripts. Integrative Oncogenomics Cancer Browser(Intro Gen) analysis shows downregulation of COX-2 and ampli?cation of MIF and/or p53 activity during development of glioblastomas,ependymoma, and colon adenomas. These data indicate the functional role of the MIF-COXp53 axis in in?ammation and cancer at the genomic and proteomic levels in COX-2-ablated cells.This systematic analysis not only shows the proin?ammatory state but also unveils a molecular signature of a pro-oncogenic state of COX-1 in COX-2 ablated cells. | Mandar Dave Abul B.M.M.K.Islam Roderick V.Jensen Agueda Rostagno Jorge Ghiso Ashok R.Amin | 2017 | Genomics, Proteomics & Bioinformatics2017，15，6： | 2 |
| 2 | Genomic,Lipidomic,and Metabolomic Analysis of Cyclooxygenase-null Cells:Eicosanoid Storm,Cross Talk,and Compensation by COX-1显示文摘The constitutively-expressed cyclooxygenase 1(COX-1) and the inducible COX-2 are both involved in the conversion of arachidonic acid(AA) to prostaglandins(PGs).However,the functional roles of COX-1 at the cellular level remain unclear.We hypothesized that by comparing differential gene expression and eicosanoid metabolism in lung fibroblasts from wild-type(WT) mice and COX-2^(-/-) or COX-1^(-/-) mice may help address the functional roles of COX-1 in inflammation and other cellular functions.Compared to WT,the number of specifically-induced transcripts were altered descendingly as follows:COX-2^(-/-) > COX-1^(-/-) > WT + IL-1β.COX-1^(-/-) or COX-2^(-/-) cells shared about 50%of the induced transcripts with WT cells treated with IL-1β,respectively.An interactive 'anti-inflammatory,proinflammatory,and redox-activated' signature in the protein-protein interactome map was observed in COX-2^(-/-) cells.The augmented COX-1mRNA(in COX-2^(-/-) cells) was associated with the upregulation of mRNAs for glutathione S-transferase(GST),superoxide dismutase(SOD),NAD(P)H dehydrogenase quinone 1(NQO1),aryl hydrocarbon receptor(AhR),peroxiredoxin,phospholipase,prostacyclin synthase,and prostaglandin E synthase,resulting in a significant increase in the levels of PGE_2,PGD_2,leukotriene B_4(LTB_4),PGF_(1α),thromboxane B_2(TXB_2),and PGF_(2α).The COX-1 plays a dominant role in shifting AA toward the LTB_4 pathway and anti-inflammatory activities.Compared to WT,the upregulated COX-1 mRNA in COX-2^(-/-) cells generated an 'eicosanoid storm'.The genomic characteristics of COX-2^(-/-) is similar to that of proinflammatory cells as observed in IL-1β induced WT cells.COX-1^(-/-) and COX-2^(-/-) cells exhibited compensation of various eicosanoids at the genomic and metabolic levels. | Abul B.M.M.K.Islam Mandar Dave Sonia Amin Roderick V.Jensen Ashok R.Amin | 2016 | Genomics, Proteomics & Bioinformatics2016，14，2： | 0 |
您所在的机构暂未开通此部分的功能，请联系管理员