Radiotherapy effect by phosphoproteomics
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Juan Dubrot
PROVIDER: PXD056537 | JPOST Repository | Wed Feb 25 00:00:00 GMT 2026
REPOSITORIES: jPOST
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Project description:Phosphoinositide 3-kinase (PI3K) signaling activation is frequently observed in triple negative breast cancer, however, PI3K inhibitors have shown limited clinical activity. To investigate resistance mechanisms, we performed global transcriptome, proteome, phosphoproteome and kinome analysis of a panel of triple negative breast cancer patient derived xenograft models with varying responsiveness to buparlisib, a pan-PI3K inhibitor, for differentially expressed baseline and post-treatment biomarkers. Resistance was associated with incomplete inhibition of PI3K and upregulated MAPK/MEK signaling in response to buparlisib. Outlier phosphoproteome and kinome analyses identified additional candidates in association with buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAPK2K4 reduced both baseline and feedback MAPK/MEK signaling and enhanced buparlisib efficacy in vitro. Interestingly, we show that a complex ins/del in PIK3CA led to a change in buparlisib response in a NEK9/MAP2K4 dependent manner. In summary, our study indicates a role for NEK9 and MAP2K4 in mediating buparlisib resistance and demonstrates the value of unbiased global analyses in uncovering resistance mechanisms to targeted therapy.
2018-05-29 | GSE100567 | GEO
Project description:Obesity is tightly linked to hepatic steatosis and insulin resistance. One feature of this association is the paradox of selective insulin resistance: insulin fails to suppress hepatic gluconeogenesis but activates lipid synthesis in the liver. How lipid accumulation interferes selectively with some branches of hepatic insulin signaling is not well understood. Here we provide a resource, based on unbiased approaches and established in a simple cell culture system, to enable investigations of the phenomenon of selective insulin resistance. We analyzed the phosphoproteome of insulin treated human hepatoma cells and identified sites in which palmitate selectively impairs insulin signaling. As an example, we show that palmitate interferes with insulin signaling to FoxO1, a key transcription factor regulating gluconeogenesis, and identify a possible mechanism. This model system, together with our comprehensive characterization of the proteome, phosphoproteome, and lipidome changes in response to palmitate treatment, provides a novel and useful resource for unraveling the mechanisms underlying selective insulin resistance.
2018-04-26 | MTBLS582 | MetaboLights
Project description:Reversible protein phosphorylation serves as a basis for regulating a number of cellular processes. Aberrant activation of kinase signaling pathways is commonly associated with several cancers. Recent developments in phosphoprotein/phosphopeptide enrichment strategies and quantitative mass spectrometry have resulted in robust pipelines for high-throughput characterization of phosphorylation in a global fashion. Today, it is possible to profile site-specific phosphorylation events on thousands of proteins in a single experiment. The potential of this approach is already being realized to characterize signaling pathways that govern oncogenesis. In addition, chemical proteomic strategies have been used to unravel targets of kinase inhibitors, which are otherwise difficult to characterize. This review summarizes various approaches used for analysis of the phosphoproteome in general, and protein kinases in particular, highlighting key cancer phosphoproteomic studies.
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Project description:Quantitative phosphoproteome and transcriptome analysis of ligand-stimulated MCF-7 human breast cancer cells was performed to understand the mechanisms of tamoxifen resistance at a systems level. Phosphoproteome data revealed that wild type (WT) cells were more enriched with phospho-proteins than tamoxifen-resistant (TamR) cells after stimulation with ligands. Surprisingly, decreased phosphorylation after ligand perturbation was more common than increased phosphorylation. In particular, 17beta-estradiol (E2) induced down-regulation in WT cells at a very high rate. E2 and the ErbB ligand, heregulin (HRG) induced almost equal numbers of up-regulated phospho-proteins in WT cells. Pathway and motif activity analyses using transcriptome data additionally suggested that deregulated activation of GSK3B?(glycogen synthase kinase 3 beta) and MAPK1/3 signaling might be associated with altered activation of CREB and AP-1 transcription factors in TamR cells and this hypothesis was validated by reporter assays. An examination of clinical samples revealed that, inhibitory phosphorylation of GSK3B at serine 9 was significantly lower in tamoxifen-treated breast cancer patients that eventually had relapses, implying that activation of GSK3B may be associated with the tamoxifen resistant phenotype. Thus, the combined phosphoproteome and transcriptome dataset analyses revealed distinct signal-transcription programs in tumor cells and provided a novel molecular target to understand tamoxifen resistance. The MCF-7 human breast cancer cell line and tamoxifen-resistant MCF-7 cells were stimulated by the growth hormone heregulin (HRG) or 17beta-estradiol (E2) in the presence or absence of tamoxifen. Control was set as non-treated cells.
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Project description:Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges forin vivoapplications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems, and warrant further investigation into adapting these approaches forin vivoage reversal.
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Project description:Fast global phosphoproteome profiling by HIFU-TiO2-SCX-LC-MS/MS
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Project description:We used state of the art mass spectrometry (MS) and RNA sequencing (RNA-Seq) to provide the first integrated proteomic, phosphoproteomic and transcriptomic atlas of the animal model Mus musculu . We measured 66 murine pancreatic ductal adenocarcinoma cell lines (66 proteomes and 66 phosphoproteome) and 41 healthy tissues (41 proteomes, 41 phosphoproteome, and 29 transcriptomes). The employed MS-based and bioinformatics strategy identified >17,000 proteins and >50,000 phosphorylation sites, providing expression evidence for ~76% of the 22,437 protein-coding genes reported in UniProtKB. The RNA-Seq strategy resulted in the quantification of 21,261 unique gene that were expressed in at least one of the 29 sequenced tissue.
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