Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA91511 | ENA |
REPOSITORIES: ENA
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Project description:Initiation of adipocyte differentiation is promoted by the synergistic action of insulin/insulin-like growth factor, glucocorticoids, and agents activating cAMP-dependent signaling. The action of cAMP is mediated via PKA and Epac, where at least part of the PKA function relates to strong repression of Rho kinase activity, whereas Epac counteracts the reduction in insulin/insulin-like growth factor signaling associated with complete repression of Rho kinase activity. However, detailed knowledge of the Epac-dependent branch and the interplay with PKA is still limited. In the present study, we present a comprehensive evaluation of Epac-mediated processes and their interplay with PKA during the initiation of 3T3-L1 preadipocyte differentiation using a combination of proteomics, molecular approaches and bioinformatics. Proteomic analyses revealed 7 proteins specifically regulated in response to Epac activation, 4 in response to PKA activation, and 11 in response to the combined activation by Epac and PKA during the initial phase of differentiation. Network analyses indicated that the identified proteins are involved in pathways of importance for glucose metabolism, inositol metabolism and calcium-dependent signaling thereby adding a novel facet to our understanding of cAMP-mediated potentiation of adipocyte differentiation.
2014-09-22 | PXD001063 | Pride
Project description:Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature
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Project description:Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we utilized a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho-proteins associated with endocytosis by the wild-type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical STAT3, STAT5 and MAPK phosphorylation, and aberrant activation of Bruton’s Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (5-fold lower IC50) for Ibrutinib-based chemical inhibition of Btk. Finally, primary murine progenitor cells from G-CSFR-d715x knock-in mice validate activation of Btk by the mutant receptor, and display enhanced sensitivity to Ibrutinib. Together, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid leukemia bearing CSF3R mutations.
2018-07-11 | PXD009662 | Pride
Project description:Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [Methylation]
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Project description:Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [Agilent]
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Project description:Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [ChIP-Seq]
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Project description:Chronic growth factor signaling in Acute Myeloid Leukemia is connected to a specific chromatin signature [DNAse-Seq]
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Project description:Neutrophil production and function are primarily determined by granulocyte colony stimulating factor receptor (G-CSFR). G-CSFRs associated mutations (mostly localized in the transmembrane and cytoplasmic domains of the receptor) have been reported with several distinct hematological abnormalities as well as malignancies, e.g. severe congenital neutropenia (SCN), acute myeloid leukemia (AML) and chronic neutrophilic leukemia (CNL). Ibrutinib, a small molecule Bruton’s tyrosine kinase (BTK) inhibitor, is FDA approved and clinically used against B-cell related leukemia. In our previous published work (Dwivedi et al., Leukemia.2019;33:75–87), we have shown ibrutinib’s efficacy in the mutated G-CSFRs based leukemia model systems (mouse and human). However, the signaling mechanism of ibrutinib’s efficacy is not explored yet. Here, we present a unique SWATH-based label free quantitative proteomics analysis of the normal and mutated G-CSFRs signaling post ibrutinib treatment, using 32D cell-line-based in vitro model system.
2020-04-27 | PXD013402 | Pride
Project description:Combined gene expression and DNA occupancy profiling identifies JAK/STAT signaling as a valid therapeutic target of t(8;21) AML t(8;21) is commonly associated with acute myeloid leukemia (AML). The resulting AML1-ETO fusion proteins are involved in the pathogenesis of AML. To identify novel molecular and therapeutic targets, we performed combined gene expression and promoter occupancy profiling using a primary leukemia initiating cell-enriched population induced by AML1-ETO9a (AE9a). CD45, a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, is greatly downregulated; furthermore JAK1 and JAK2 are upregulated in these leukemia cells. Consequently, JAK/STAT signaling is enhanced in the AE9a leukemia cells. Importantly, AE9a leukemia cells are highly susceptible to perturbation of JAK/STAT signaling, and a JAK2-selective inhibitor, TG101209, effectively targets these leukemia cells in vivo, suggesting the potential efficacy of JAK2 inhibitors in treating t(8;21) AML. Wild-type or AE9a leukemic samples in triplicate.
2012-09-04 | E-GEOD-15195 | biostudies-arrayexpress
Project description:Granulocyte colony stimulating factor receptor (G-CSFR) plays important role in the production of neutrophils from hematopoietic stem cells. Mutated form of the receptor has been directly associated with two distinct malignant phenotype in patients, e.g. acute myeloid leukemia (AML) and chronic neutrophilic leukemia (CNL). However, the signaling mechanism of the mutated G-CSFRs is not well understood. Here, we describe a comprehensive SILAC based quantitative phosphoproteomic analysis of the mutated G-CSFRs compared to the normal receptor using BaF3 cell line based in vitro model system. High pH reversed phase concatenation and Titanium Dioxide Spin Tip column were utilized to increase the dynamic range and detection of the phosphoproteome of G-CSFRs. The dataset was further analyzed using several computational and bioinformatics tools. Overall, this dataset is a first of any phosphoproteomics analysis of granulocyte colony stimulating factor receptors in the normal and disease associated mutations. We anticipate that our dataset will have a strong potential to decipher the phospho-signaling differences between the normal and malignant G-CSFR biology with therapeutic implications.
2019-02-14 | PXD009311 | Pride