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Dynamic proteomics reveals unexpected plasticity of cellular proteome

ABSTRACT: In proteomics, the changes occurring in cellular proteomes upon drug treatment are used to identify the drug targets and the mechanism of action. However, proteomes of cultured cells undergo also natural alteration associated with changes in the media, attaining a degree of confluence as well as due to cell division, metabolic and circadian cycles. These changes are implicitly assumed to be minimal. In this study, we tested this assumption experimentally by comparing the proteome dynamics of untreated HCT116 and A375 cancer cells during 48 h. Time series revealed considerable growth-related proteome changes. The magnitude of these variations reveals an unexpected plasticity of the cellular proteome and reinforces the need, generally accepted in theory but not always followed in practice, to use a time-matched control when measuring drug-induced proteome changes.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Colon Cancer,Melanoma

SUBMITTER: Pierre Sabatier

LAB HEAD: Roman Zubarev

PROVIDER: PXD010805 | Pride | 2018-11-07

REPOSITORIES: Pride

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Dynamic proteomics reveals unexpected plasticity of cellular proteome: growth-related and drug-induced changes in cancer cells are comparable

Project description:In proteomics, the changes occurring in cellular proteomes upon drug treatment are used to identify the drug targets and the mechanism of action. However, proteomes of cultured cells undergo also natural alteration associated with changes in the media, attaining a degree of confluence as well as due to cell division, metabolic and circadian cycles. These changes are implicitly assumed to be smaller in magnitude than the drug-induced changes that ultimately lead to cell demise. In this study, we tested this assumption experimentally by comparing the proteome dynamics of cancer cells during the first 48 h after treatment with methotrexate, paclitaxel or vehicle (equivalent to untreated control). Time series revealed considerable growth-related proteome changes in the control group, comparable in magnitude to drug-induced changes. The magnitude of these variations reveals an unexpected plasticity of the cellular proteome and reinforces the need, generally accepted in theory but not always followed in practice, to use a time-matched control when measuring drug-induced proteome changes.

2018-11-07 | PXD007762 | Pride

Polymorphism in estrogen receptor binding site causes CD2-dependent sex bias in T cell autoimmune diseases

Project description:Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors likely determines the sex discrepancy in the immune response, but conclusive evidence regarding the underlying molecular mechanisms is lacking. Using forward genetics, we positionally identified a polymorphic estrogen receptor binding site that regulates CD2 expression, leading to female-specific differences in mouse models of T cell-dependent autoimmunity. Female mice with reduced CD2 levels displayed a diminished T cell activation and autoimmune T cell response. Mechanistically, CD2 affected LAG-3 expression. Our findings help to explain the sexual dimorphism in human autoimmunity, as CD2 associated with rheumatoid arthritis and its regulation through 17-β-estradiol was conserved in human T cells. Hormonal regulation of CD2 has implications for CD2-targeted therapy. Indeed, anti-CD2 treatment more potently affected female mice. In conclusion, our results demonstrate the relevance of sex-genotype interactions and deliver strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.

2021-07-15 | PXD024126 | Pride

Polymorphisms of the vitamin D receptor regulate T cells and T cell dependent inflammatory diseases

Project description:Complex autoimmune diseases have proven difficult to dissect down to their causative genetic mechanisms. As a result, epidemiological data from different human association studies are often merged to arrive at a working hypothesis. In one of such examples, lack of sun exposure and consequent lower serum vitamin D3 levels has been proposed to increase risk of autoimmunity, attributing vitamin D3 an immune regulatory role. However, conclusive evidence demonstrating its efficacy in treating autoimmune diseases is missing. In this study, we have used a forward genetics approach to positionally identify polymorphic nucleotides controlling T cell-dependent inflammatory diseases using congenic mouse strains. Here, we identify the vitamin D3 receptor (Vdr) as a driver of inflammation. Congenic mice carrying a polymorphic Vdr allele overexpressed the receptor selectively in activated T cells, thereby escaping systemic calcaemic side effects that often constitute a confounding factor in the study of immunomodulation by vitamin D3. Mice overexpressing Vdr in T cells developed more severe collagen-induced arthritis (CIA) and exhibited an enhanced antigen-specific CD4+ T cell response. Deficiency of vitamin D3 completely protected mice from CIA by limiting the activation of antigen-specific T cell responses, and arthritis susceptibility was restored by re-administration of vitamin D3. We demonstrate that vitamin D3 signalling specifically through Vdr predominantly acts to enhance T cell proliferation, thereby contributing to inflammation. In conclusion, our results demonstrate that genetically determined expression of VDR codetermines the pro-inflammatory behaviour of activated T cells. Furthermore, our data suggest that the anti-inflammatory properties of vitamin D3 might be limited by high expression of VDR at the site of inflammation.

2020-09-28 | PXD019876 | Pride

Comprehensive chemical proteomics analyses reveal that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than Auranofin

Project description:Anticancer drugs that target cellular antioxidant systems have recently attracted much attention. Auranofin (AF) is currently evaluated in several clinical trials as an anticancer agent and targets the cytosolic and mitochondrial forms of the selenoprotein thioredoxin reductase, Txnrd1 and Txnrd2. Recently, two novel Txnrd1 inhibitors (TRi-1 and TRi-2) have been developed that showed anticancer efficacy comparable to AF, but with lower mitochondrial toxicity. However, the cellular action mechanisms of these drugs have not yet been thoroughly studied. Here we used several proteomics analyses to determine the effects of AF, TRi-1 and TRi-2 when used at IC50 concentrations with the mouse B16 melanoma and LLC lung adenocarcinoma cells, as these are often used for preclinical mouse models in evaluation of anticancer drugs. The results demonstrate that TRi-1 and TRi-2 are more specific Txnrd1 inhibitors than AF and reveal additional AF-specific effects on the cellular proteome. Interestingly, AF triggered stronger Nrf2-driven antioxidant responses than the other two compounds. Furthermore, AF affected several additional proteins, including Gsk3a, Gsk3b, Mcmbp and Eefsec, implicating additional effects on glycogen metabolism, cellular differentiation, inflammatory pathways, DNA replication and selenoprotein synthesis processes. Our proteomics data should represent a resource for researchers interested in the multidimensional analysis of proteome changes associated with oxidative stress in general, and the effects of Txnrd inhibitors and AF protein targets in particular.

2021-12-15 | PXD028398 | Pride

Expression data of CD117+ splenocytes from C57BL/6 WT and RasGRP4 KO mice upon LPS stimulation

Project description:RasGRP4 is required for CD117+ DCs to optimally induce certain NK cell-dependent immune responses in vivo and in vitro in response to LPSRasGRP4 expressed in DCs played an important role on NK cell IFN-γ secretion . We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated or down-regulated genes between the two DCs from WT and RasGRP4 mice respectively upon LPS stimulation. CD117+splenocytes were extracted from WT and RasGRP4 KO mice spleens aged 9-12 weeks and plated in 6-well plates with 1ug/mL of LPS for 0h,6h,12h,24h and 48h repectively for RNA extraction and hybridization on Affymetrix microarrays. Time course.

2015-05-19 | E-GEOD-69011 | biostudies-arrayexpress

Transcription profiling of QUB HCT116 sensitive and resistant colorectal cancer time series

Project description:HCT116 parental, HCT116 5-FU resistant and HCT116 oxaliplatin resistant cells have been transiently treated with with their respective drug (5-FU or oxaliplatin) for 0, 6 12 or 24h in 3 independent experiments.

2006-01-01 | E-MEXP-390 | biostudies-arrayexpress

Transcription profiling of human HCT116 parental cells treated with 5-FU or SN38 and non-treated parental cells, 5-FU resistant and SN39 resistant cells

Project description:The transcriptional profiles of the HCT116 parental cells following treatment with either 5-FU or SN38 for 24h were assessed. In addition, basal comparisons between HCT116 parental and HCT116 5-FU -resistant and HCT116 SN38-resistant cells were also assessed.

2009-03-30 | E-MEXP-1691 | biostudies-arrayexpress

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2021-10-05 | PXD018453 | Pride

Mycoplasma Pneumoniae transcriptome along Growth Curve

Project description:To gain insight into ncRNAs functionality in bacteria, we studied the correlation of gene expression from Mycoplasma pneumoniae's ncRNAs with their overlapping ORFs over 10 different time points. This experiment contains RNAseq pair-end data from this 10 time points along Mycoplasma pneumoniae growth cycle.

2015-07-09 | E-MTAB-3076 | biostudies-arrayexpress

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2015-06-30 | E-MTAB-2689 | biostudies-arrayexpress

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