Identifying disease-specific genes based on their topological significance in protein networks

Dezső, Zoltán; Nikolsky, Yuri; Nikolskaya, Tatiana; Miller, Jeremy; Cherba, David; Webb, Craig P.; Bugrim, Andrej

doi:10.1186/1752-0509-3-36

Cited by 113 publications

(92 citation statements)

References 32 publications

(29 reference statements)

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“…Calcium binds calmodulin followed by CaMKII activation. Both PKC␦ and CaMKII can serine phosphorylate S727 on STAT1 which is required for full transcriptional activity of the STAT1 dimer (418,1420).…”

Section: Macrophage Phenotypes: Artificial But Useful Constructs Basementioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Macrophage Phenotypes: Artificial But Useful Constructs Basementioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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“…Expression data were collected for each organism from previously published data, and genes lacking expression data were removed from the study [A. thaliana (Carviel et al 2009); C. elegans, Michael Smith Genome Sciences Centre (http://www.bcgsc.ca) D. melanogaster, FlyAtlas (http://www. flyatlas.org) (Chintapalli et al 2007); H. sapiens (Dezso et al 2009); S. cerevisiae (Pelechano et al 2010); and S. pombe (Tanizawa et al 2010)]. Remaining genes (Table 1) were then used for analysis.…”

Section: Data Collectionmentioning

confidence: 99%

Selection on Position of Nonsense Codons in Introns

Behringer

Hall

2016

Genetics

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Introns occasionally remain in mature messenger RNAs (mRNAs) due to splicing errors and the translated, aberrant proteins that result represent a metabolic cost and may have other deleterious consequences. The nonsense-mediated decay (NMD) pathway degrades aberrant mRNAs, which it recognizes by the presence of an in-frame premature termination codon (PTC). We investigated whether selection has shaped the location of PTCs in introns to reduce waste and facilitate NMD. We found across seven model organisms, that in both first and last introns, PTCs occur earlier in introns than expected by chance, suggesting that selection favors earlier position. This pattern is more pronounced in species with larger effective population sizes. The pattern does not hold for last introns in the two mammal species, however, perhaps because in these species NMD is not initiated from 39-terminal introns. We conclude that there is compelling evidence that the location of PTCs is shaped by selection for reduced waste and efficient degradation of aberrant mRNAs.KEYWORDS premature termination codon; nonsense-mediated decay; translation; splicing errors; intron definition I T is clear that selection can play a major role in shaping genome architecture (Lynch 2007). Identifying selection is especially straightforward for exons in protein coding genes, where tests based on silent and replacement site substitutions can be employed. However, in noncoding regions, the role of selection in shaping nucleotide content is less easily investigated because of the difficulty identifying expected patterns. In introns, length, phase, and frequency of occurrence have been studied as a product of the processes of selection and drift (Castillo-Davis et al. 2002;Lynch 2002;Whitney and Garland 2010;Kelkar and Ochman 2012) but, apart from sequence-based splicing signals and GC content (Mount 1982;Deutsch and Long 1999;Amit et al. 2012;Farlow et al. 2012), few studies have examined the nucleotide composition of introns (Lim and Burge 2001;Halligan et al. 2004;Andolfatto 2005;Ressayre et al. 2015). In this study, we investigate the role of selection in determining the position of premature termination codons (PTCs) within introns.During post-transcriptional processing, splicing errors can result in introns being present in mature messenger RNAs (mRNAs) (Gilbert 1978). Translation of such mRNAs results in the production of proteins that are aberrant in amino acid sequence and usually shortened. A shorter protein results from the presence of in-frame, PTCs within the unspliced intron, or in a downstream exon due to a frameshift. Aberrant proteins may reduce fitness because they have an activity that is damaging to the cell, and/or because they represent wasted resources, particularly amino acids and sequestered ribosomes (Drummond and Wilke 2009). For these reasons, we hypothesize that selection favors both efficient splicing and mechanisms that minimize the effects of splicing errors.There is strong evidence for selection acting on both the efficiency ...

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“…An application of computational methods can be seen in Protein kinases that control cellular decision processes by phosphorylating specific substrates. Since proteome-wide mapping has identified thousands of in vivo phosphorylation sites, a computational method, NetworKIN, can augment motifs with context for kinases and phosphoproteins and yields a 2.5-fold improvement in the accuracy which can be used in constructing phosphorylation networks [13,14].…”

Section: Protein Network In Diseasesmentioning

confidence: 99%

Protein networks in diseases

NA¹,

SG²,

BD³

et al. 2009

Int J of Drug Disc

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Abstract-Protein interactions and their specificity play important roles in protein structure and functions. Identification and characterization of protein interfaces is thus important for the study. Adhesive interactions can be considered as one of the key features of many interactions. Computational approach can be applied to great extent in identifying disease specific genes. For instance, Nfat and tat proteins have specific roles related to diseases whose roles can be studied. Apoptosis is considered as a crucial part of many cellular activities and is shown to be related to proteolysis, inflammatory responses, in cancer perturbed protein interaction and mitochondrial dynamics.

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Identifying disease-specific genes based on their topological significance in protein networks

Cited by 113 publications

References 32 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

Selection on Position of Nonsense Codons in Introns

Protein networks in diseases

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