Dataset Information

A Compendium of Co-regulated Protein Complexes in Breast Cancer Reveals Collateral Loss Events.

ABSTRACT: Protein complexes are responsible for the bulk of activities within the cell, but how their behavior and abundance varies across tumors remains poorly understood. By combining proteomic profiles of breast tumors with a large-scale protein-protein interaction network, we have identified a set of 285 high-confidence protein complexes whose subunits have highly correlated protein abundance across tumor samples. We used this set to identify complexes that are reproducibly under- or overexpressed in specific breast cancer subtypes. We found that mutation or deletion of one subunit of a co-regulated complex was often associated with a collateral reduction in protein expression of additional complex members. This collateral loss phenomenon was typically evident from proteomic, but not transcriptomic, profiles, suggesting post-transcriptional control. Mutation of the tumor suppressor E-cadherin (CDH1) was associated with a collateral loss of members of the adherens junction complex, an effect we validated using an engineered model of E-cadherin loss.

SUBMITTER: Ryan CJ

PROVIDER: S-EPMC5660599 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A Compendium of Co-regulated Protein Complexes in Breast Cancer Reveals Collateral Loss Events.

Ryan Colm J CJ Kennedy Susan S Bajrami Ilirjana I Matallanas David D Lord Christopher J CJ

Cell systems 20171011 4

Protein complexes are responsible for the bulk of activities within the cell, but how their behavior and abundance varies across tumors remains poorly understood. By combining proteomic profiles of breast tumors with a large-scale protein-protein interaction network, we have identified a set of 285 high-confidence protein complexes whose subunits have highly correlated protein abundance across tumor samples. We used this set to identify complexes that are reproducibly under- or overexpressed in ...[more]

PMID: 29032073

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Project description:BackgroundProteins interacting with each other as a complex play an important role in many molecular processes and functions. Directly detecting protein complexes is still costly, whereas many protein-protein interaction (PPI) maps for model organisms are available owing to the fast development of high-throughput PPI detecting techniques. These binary PPI data provides fundamental and abundant information for inferring new protein complexes. However, PPI data from different experiments do not overlap very much usually. The main reason is that the functions of proteins can activate only on certain environment or stimulus. In a short, PPI is condition-specific. Therefore specifying the conditions on when complexes are present is necessary for a deep understanding of their behaviours. Meanwhile, proteins have various interaction ways and control mechanisms to form different kinds of complexes. Thus the discovery of a certain type of complexes should depend on their own distinct biological or topological characteristics. We do not attempt to find all kinds of complexes by using certain features. Here, we integrate transcription regulation data (TR), gene expression data (GE) and protein-protein interaction data at the systems biology level to discover a special kind of protein complex called conditional co-regulated protein complexes. A conditional co-regulated protein complex has three remarkable features: the coding genes of the member proteins share the same transcription factor (TF), under a certain condition the coding genes express co-ordinately and the member proteins interact mutually as a complex to implement a common biological function.ResultsA framework of discovering the conditional co-regulated protein complexes is proposed. Testing on the Yeast data sets under the Cell Cycle, DNA Damage and Dauxic Shift conditions, we identified a total of 29 conditional co-regulated complexes, among which the coding genes in 14 complexes show a strong association with their TFs activity. Based on the close relationship among co-regulation, co-expression and protein-protein interactions in the conditional co-regulated protein complexes, 39 novel TRs were predicted and explained.ConclusionsThis paper was initiated to study conditional co-regulated protein complexes by integrating multiple data sources. Taking into consideration the influence of TFs activity on the protein interactions, we found that the expression coherence of the protein complexes' coding genes changed in accordance to their TFs' activity, which implied that the proteins' interactions also changed in response to the environments. Based on the three features of conditional co-regulated protein complexes, new transcriptional regulation interactions were predicted.

Project description:Serine/threonine protein phosphatase 1 regulatory subunit 12A (PPP1R12A) modulates the activity and specificity of the catalytic subunit of protein phosphatase 1, regulating various cellular processes via dephosphorylation. Nonetheless, little is known about phosphorylation events controlled by PPP1R12A in skeletal muscle insulin signaling. Here, we used quantitative phosphoproteomics to generate a global picture of phosphorylation events regulated by PPP1R12A in a L6 skeletal muscle cell line, which were engineered for inducible PPP1R12A knockdown. Phosphoproteomics revealed 3876 phosphorylation sites (620 were novel) in these cells. Furthermore, PPP1R12A knockdown resulted in increased overall phosphorylation in L6 cells at the basal condition, and changed phosphorylation levels for 698 sites (assigned to 295 phosphoproteins) at the basal and/or insulin-stimulated conditions. Pathway analysis on the 295 phosphoproteins revealed multiple significantly enriched pathways related to insulin signaling, such as mTOR signaling and RhoA signaling. Moreover, phosphorylation levels for numerous regulatory sites in these pathways were significantly changed due to PPP1R12A knockdown. These results indicate that PPP1R12A indeed plays a role in skeletal muscle insulin signaling, providing novel insights into the biology of insulin action. This new information may facilitate the design of experiments to better understand mechanisms underlying skeletal muscle insulin resistance and type 2 diabetes.Biological significanceThese results identify a large number of potential new substrates of serine/threonine protein phosphatase 1 and suggest that serine/threonine protein phosphatase 1 regulatory subunit 12A indeed plays a regulatory role in multiple pathways related to insulin action, providing novel insights into the biology of skeletal muscle insulin signaling. This information may facilitate the design of experiments to better understand the molecular mechanism responsible for skeletal muscle insulin resistance and associated diseases, such as type 2 diabetes and cardiovascular diseases.

Project description:BackgroundHypoxia and temperature stress are two major adverse environmental conditions often encountered by fishes. The interaction between hypoxia and temperature stresses has been well documented and oxygen is considered to be the limiting factor for the thermal tolerance of fish. Although both high and low temperature stresses can impair the cardiovascular function and the cross-resistance between hypoxia and heat stress has been found, it is not clear whether hypoxia acclimation can protect fish from cold injury.ResultsPre-acclimation of 96-hpf zebrafish larvae to mild hypoxia (5% O2) significantly improved their resistance to lethal hypoxia (2.5% O2) and increased the survival rate of zebrafish larvae after lethal cold (10°C) exposure. However, pre-acclimation of 96-hpf larvae to cold (18°C) decreased their tolerance to lethal hypoxia although their ability to endure lethal cold increased. RNA-seq analysis identified 132 up-regulated and 41 down-regulated genes upon mild hypoxia exposure. Gene ontology enrichment analyses revealed that genes up-regulated by hypoxia are primarily involved in oxygen transport, oxidation-reduction process, hemoglobin biosynthetic process, erythrocyte development and cellular iron ion homeostasis. Hypoxia-inhibited genes are enriched in inorganic anion transport, sodium ion transport, very long-chain fatty acid biosynthetic process and cytidine deamination. A comparison with the dataset of cold-regulated gene expression identified 23 genes co-induced by hypoxia and cold and these genes are mainly associated with oxidation-reduction process, oxygen transport, hemopoiesis, hemoglobin biosynthetic process and cellular iron ion homeostasis. The alleviation of lipid peroxidation damage by both cold- and hypoxia-acclimation upon lethal cold stress suggests the association of these genes with cold resistance. Furthermore, the alternative promoter of hmbsb gene specifically activated by hypoxia and cold was identified and confirmed.ConclusionsAcclimation responses to mild hypoxia and cold stress were found in zebrafish larvae and pre-acclimation to hypoxia significantly improved the tolerance of larvae to lethal cold stress. RNA-seq and bioinformatics analyses revealed the biological processes associated with hypoxia acclimation. Transcriptional events co-induced by hypoxia and cold may represent the molecular basis underlying the protection of hypoxia-acclimation against cold injury.

Dataset Information

A Compendium of Co-regulated Protein Complexes in Breast Cancer Reveals Collateral Loss Events.

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A Compendium of Co-regulated Protein Complexes in Breast Cancer Reveals Collateral Loss Events.

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