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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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			Action	DRS
	2018_07_26_Time_serie_AC1-1.raw	Raw
	2018_07_26_Time_serie_AC1-10.raw	Raw
	2018_07_26_Time_serie_AC1-11.raw	Raw
	2018_07_26_Time_serie_AC1-12.raw	Raw
	2018_07_26_Time_serie_AC1-13.raw	Raw

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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.

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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.

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

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