Can we predict protein from mRNA levels?

Fortelny, Nikolaus; Overall, Christopher M.; Pavlidis, Paul; Freue, Gabriela V. Cohen

doi:10.1038/nature22293

Cited by 187 publications

(178 citation statements)

References 7 publications

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“…This number is in the range of several other FFPE-based proteomic studies [30], [31], [33]. Limited proteome overlap between biological and technical replicates continues to be a characteristic limitation of explorative shotgun proteomics [26], [27]. Although each case allowed for the identification and quantification of a comparable number of proteins (Figure 2 A ), the number of proteins that were consistently observed in all 12 samples remained below 600 (Supplementary Figure 1 A ).…”

Section: Resultsmentioning

confidence: 85%

“…Coupled with label-free shotgun proteomics and immunohistochemistry, these FFPE tissues have been widely used to identify biomarkers and drug targets in different disease settings [22], [23], [24], [25]. Several recent reports highlight a limited correlation between mRNA levels and corresponding protein levels, thus arguing in favor of proteomic approaches [26], [27]. In PDAC, drug combination therapies have been experimented to improve treatment efficacy.…”

Section: Introductionmentioning

confidence: 99%

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Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance

Oria

Bronsert

Thomsen

et al. 2018

Translational Oncology

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Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.

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Section: Resultsmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance

Oria

Bronsert

Thomsen

et al. 2018

Translational Oncology

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“…We note that correlation between RNA abundances and protein abundances is a subject of extensive discussions and generally low (e.g. (40)), but the completeness of RNA abundances is far higher and enables nearly complete comparisons with several protein sets. In Table 1 we show the relative distributions of proteins within these high, medium, low and not detected categories.…”

Section: Comparisons With Rna Abundancesmentioning

confidence: 99%

The Human Plasma Proteome Draft of 2017: Building on the Human Plasma PeptideAtlas from Mass Spectrometry and Complementary Assays

et al. 2017

Self Cite

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Human blood plasma provides a highly accessible window to the proteome of any individual in health and disease. Since its inception in 2002, the Human Proteome Organization’s Human Plasma Proteome Project (HPPP) has been promoting advances in the study and understanding of the full protein complement of human plasma and on determining the abundance and modifications of its components. In 2017, we review the history of the HPPP and the advances of human plasma proteomics in general, including several recent achievements. We then present the latest 2017-04 build of Human Plasma PeptideAtlas, which yields ~43 million peptide-spectrum matches and 122,730 distinct peptide sequences from 178 individual experiments at a 1% protein-level FDR globally across all experiments. Applying the latest Human Proteome Project Data Interpretation Guidelines, we catalog 3509 proteins that have at least two non-nested uniquely-mapping peptides of 9 amino acids or more and >1300 additional proteins with ambiguous evidence. We apply the same two-peptide guideline to historical PeptideAtlas builds going back to 2006 and examine the progress made in the past ten years in plasma proteome coverage. We also compare the distribution of proteins in historical PeptideAtlas builds in various RNA-abundance and cellular localization categories. We then discuss advances in plasma proteomics based on targeted mass spectrometry as well as affinity assays, which during early 2017 target ~2000 proteins. Finally we describe considerations about sample handling and study design, concluding with an outlook for future advances in deciphering the human plasma proteome.

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“…Yet the functional roles of most ISGs as effectors of the innate immune response remain to be fully characterized. Furthermore, in view of the limited ability of mRNA levels to predict cellular protein abundance [14,15] , the degree to which IFN-induced changes in transcriptional activity ultimately manifest at the level of the proteome remains incompletely understood. A complete understanding of the IFN signalling repertoire would include a direct interrogation of the complex network of interacting proteins that mediate the type I IFN response, beyond those with a direct role in restricting viral replication.…”

Section: Introductionmentioning

confidence: 99%

Dynamic rewiring of the human interactome by interferon signalling

Kerr

Skinnider

Madero

et al. 2019

Preprint

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Background:The type I interferon (IFN) response is an ancient pathway that protects cells against viral pathogens by inducing the transcription of hundreds of IFN-stimulated genes (ISGs). Transcriptomic and biochemical approaches have established comprehensive catalogues of ISGs across species and cell types, but their antiviral mechanisms remain incompletely characterized. Here, we apply a combination of quantitative proteomic approaches to delineate the effects of IFN signalling on the human proteome, culminating in the use of protein correlation profiling to map IFN-induced rearrangements in the human protein-protein interaction network. Results:We identified >27,000 protein interactions in IFN-stimulated and unstimulated cells, many of which involve proteins associated with human disease and are observed exclusively within the IFN-stimulated network. Differential network analysis reveals interaction rewiring across a surprisingly broad spectrum of cellular pathways in the antiviral response. We identify IFN-dependent protein-protein interactions mediating novel regulatory mechanisms at the transcriptional and translational levels, with one such interaction modulating the transcriptional activity of STAT1. Moreover, we reveal IFN-dependent changes in ribosomal composition that act to buffer ISG protein synthesis.Conclusions : Our map of the IFN interactome provides a global view of the complex cellular networks activated during the antiviral response, placing ISGs in a functional context, and serves as a framework to understand how these networks are dysregulated in autoimmune or inflammatory disease. interaction network in differential and physiologically relevant contexts at the proteome scale represents a longstanding challenge [16] .Here, we apply a combination of quantitative proteomic approaches to chart the molecular landscape of type I IFN signalling, culminating in the use of protein correlation profiling (PCP)[17] to map interferon-induced rearrangements in the human interactome. The resulting protein-protein interaction network, encompassing over 27,000 interactions, reveals widespread rewiring of physical interactions and places known ISGs in an IFN-dependent functional context.We find evidence that the most evolutionarily conserved subset of ISGs are induced to physically interact in response to IFN stimulation, and experimentally validate the role of one such interaction in modulating STAT1 transcription. We develop statistical methods for differential network analysis to characterize interactome rewiring at the functional level, leading us to identify alterations in ribosome composition induced by interferon signalling that selectively downregulate ISG synthesis in order to fine-tune the IFN response. Collectively, this differential network map of the IFN-induced interactome provides a resource to mechanistically dissect the IFN response in the context of viral infection and autoimmune disease. RESULTS Proteome-wide analysis of the type I IFN responseWhereas the transcriptional response to IFN s...

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Can we predict protein from mRNA levels?

Cited by 187 publications

References 7 publications

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance

The Human Plasma Proteome Draft of 2017: Building on the Human Plasma PeptideAtlas from Mass Spectrometry and Complementary Assays

Dynamic rewiring of the human interactome by interferon signalling

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