A Novel Systems-Biology Algorithm for the Analysis of Coordinated Protein Responses Using Quantitative Proteomics

Garcia-Marques, Fernando Jose; Trevisán-Herraz, Marco; Martı́nez-Martı́nez, Sara; Camafeita, Emilio; Jorge, Inmaculada; López, Juan Antonio; Méndez‐Barbero, Nerea; Méndez-Ferrer, Simón; Pozo, Miguel Á. del; Ibáñez, Borja; Andrés, Vicente; Sánchez-Madrid, Francisco; Redondo, Juan Miguel; Bonzón-Kulichenko, Elena; Vázquez, Jesús

doi:10.1074/mcp.m115.055905

Cited by 87 publications

(128 citation statements)

References 126 publications

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“…Since cellular processes are accomplished by proteins working together in complexes or functional pathways, we have also resorted to a systems biology model [45] to assess whether the protein abundance changes took place in a coordinated manner, a biological event that is well-known [46]. These analyses revealed that global OXPHOS down-regulation is a key hallmark of age progression in adipocyte mitochondria (Fig.…”

Section: Resultsmentioning

confidence: 99%

Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes

et al. 2017

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Human age-related diseases, including obesity and type 2 diabetes (T2DM), have long been associated to mitochondrial dysfunction; however, the role for adipose tissue mitochondria in these conditions remains unknown. We have tackled the impact of aging and T2DM on adipocyte mitochondria from obese patients by quantitating not only the corresponding abundance changes of proteins, but also the redox alterations undergone by Cys residues thereof. For that, we have resorted to a high-throughput proteomic approach based on isobaric labeling, liquid chromatography and mass spectrometry. The alterations undergone by the mitochondrial proteome revealed aging- and T2DM-specific hallmarks. Thus, while a global decrease of oxidative phosphorylation (OXPHOS) subunits was found in aging, the diabetic patients exhibited a reduction of specific OXPHOS complexes as well as an up-regulation of the anti-oxidant response. Under both conditions, evidence is shown for the first time of a link between increased thiol protein oxidation and decreased protein abundance in adipose tissue mitochondria. This association was stronger in T2DM, where OXPHOS mitochondrial- vs. nuclear-encoded protein modules were found altered, suggesting impaired mitochondrial protein translocation and complex assembly. The marked down-regulation of OXPHOS oxidized proteins and the alteration of oxidized Cys residues related to protein import through the redox-active MIA (Mitochondrial Intermembrane space Assembly) pathway support that defects in protein translocation to the mitochondria may be an important underlying mechanism for mitochondrial dysfunction in T2DM and physiological aging. The present draft of redox targets together with the quantification of protein and oxidative changes may help to better understand the role of oxidative stress in both a physiological process like aging and a pathological condition like T2DM.

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Section: Resultsmentioning

confidence: 99%

Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes

et al. 2017

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“…Pathway enrichment analysis revealed that miR-28-induced transcriptome and proteome changes grouped in remarkably similar cellular function pathways ( Figure 2E), and a class-scoring algorithm that identifies alterations in functional categories 28 showed that miR-28 expression in Ramos BL cells induces the coordinated downregulation of proteins belonging to cell-cycle progression pathways ( Figure 2F). Finally, ingenuity pathway analysis showed that proteins whose levels are altered by miR-28 form a highly significant cluster of genes involved in BCR signaling.…”

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confidence: 99%

miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma

Bartolomé-Izquierdo¹,

Yébenes²,

Álvarez-Prado³

et al. 2017

Blood

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• miR-28 is a regulator of the GC reaction that dampens B-cell receptor signaling and impairs B-cell proliferation and survival.• miR-28 has antitumoral activity in BL and DLBCL.Non-Hodgkin lymphoma comprises a variety of neoplasms, many of which arise from germinal center (GC)-experienced B cells. microRNA-28 (miR-28) is a GC-specific miRNA whose expression is lost in numerous mature B-cell neoplasms. Here we show that miR-28 regulates the GC reaction in primary B cells by impairing class switch recombination and memory B and plasma cell differentiation. Deep quantitative proteomics combined with transcriptome analysis identified miR-28 targets involved in cell-cycle and B-cell receptor signaling. Accordingly, we found that miR-28 expression diminished proliferation in primary and lymphoma cells in vitro. Importantly, miR-28 reexpression in human Burkitt (BL) and diffuse large B-cell lymphoma (DLBCL) xenografts blocked tumor growth, both when delivered in viral vectors or as synthetic, clinically amenable, molecules. Further, the antitumoral effect of miR-28 is conserved in a primary murine in vivo model of BL. Thus, miR-28 replacement is uncovered as a novel therapeutic strategy for DLBCL and BL treatment. (Blood. 2017;129(17):2408-2419

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“…Interestingly, PRC2A (Proline Rich Coiled-Coil 2A, also known as BAT2), a poorly characterized protein, strongly associated with GRB2 ∼30 s after T cell activation (fold change = 6.1; p = 3.8 × 10 −6 ) and slowly disassembled over time—a kinetic similar to the one observed for well-established components of the TCR signaling pathway, e.g., LAT, SOS1, VAV1, SLP-76/LCP2, and CBLB (Figure 3D). Since functionally related proteins may show similar kinetics of assembly-disassembly in response to cell stimulation (García-Marqués et al., 2016), this result suggests a role for PRC2A in TCR signaling. Collectively, these quantitative AP-SWATH data provided a systematic and accurate view of the temporal reorganization of the GRB2 protein interaction network after TCR-mediated activation of peripheral CD4 + T cells.…”

Section: Resultsmentioning

confidence: 99%

Precise Temporal Profiling of Signaling Complexes in Primary Cells Using SWATH Mass Spectrometry

et al. 2017

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SummarySpatiotemporal organization of protein interactions in cell signaling is a fundamental process that drives cellular functions. Given differential protein expression across tissues and developmental stages, the architecture and dynamics of signaling interaction proteomes is, likely, highly context dependent. However, current interaction information has been almost exclusively obtained from transformed cells. In this study, we applied an advanced and robust workflow combining mouse genetics and affinity purification (AP)-SWATH mass spectrometry to profile the dynamics of 53 high-confidence protein interactions in primary T cells, using the scaffold protein GRB2 as a model. The workflow also provided a sufficient level of robustness to pinpoint differential interaction dynamics between two similar, but functionally distinct, primary T cell populations. Altogether, we demonstrated that precise and reproducible quantitative measurements of protein interaction dynamics can be achieved in primary cells isolated from mammalian tissues, allowing resolution of the tissue-specific context of cell-signaling events.

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A Novel Systems-Biology Algorithm for the Analysis of Coordinated Protein Responses Using Quantitative Proteomics

Cited by 87 publications

References 126 publications

Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes

Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes

miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma

Precise Temporal Profiling of Signaling Complexes in Primary Cells Using SWATH Mass Spectrometry

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