MDAMB-231 Fusion Lumos, LC-MSMS
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Epithelial Cell, Cell Culture
DISEASE(S): Breast Cancer
SUBMITTER: 
Nikhil Gupta
LAB HEAD: Jukka Westermarck
PROVIDER: PXD035179 | Pride | 2022-10-21
REPOSITORIES: Pride
Similar Datasets
Project description:Abstract The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56 is a human tumor suppressor. However, the molecular mechanisms inhibiting PP2A-B56in cancer are poorly understood. Here, we report molecular level details and structural mechanism of PP2A-B56inhibition by an oncoprotein CIP2A. Upon direct binding to PP2A-B56 trimer, CIP2A replaces PP2A-A subunit and thereby hijacks both the B56 and the catalytic PP2Ac subunit to form a CIP2A-B56-PP2Ac pseudotrimer. Further, CIP2A competes with B56 substrate binding by blocking the LxxIxE-motif substrate binding pocket on B56. Relevant to oncogenic activity of CIP2A across human cancers, the N-terminal head domain-mediated interaction with B56 stabilizes CIP2A protein. Functionally, CRISPR/Cas9-mediated single amino acid mutagenesis of the head domain blunted MYC expression and MEK phosphorylation, and abrogated triple-negative breast cancer in vivo tumor growth. Collectively, we discover a unique multi-step “hijack and mute” mechanism of protein complex regulation inhibiting tumor suppressor PP2A-B56. Further, the results unfold single structural determinant for CIP2A´s oncogenic activity, potentially facilitating therapeutic modulation of CIP2A in cancer and other diseases.
2023-03-11 | PXD030297 | Pride
Project description:Decidualization is a progesterone-initiated differentiation concerning the endometrium and is dedicated to supporting the placenta and embryo development. During the process, cAMP signaling is widely known to be indispensable, but the details are not fully understood. In this study, we show that cAMP signaling promotes AKT deactivation in endometrial stromal cells, which favors their decidualization. The deactivation of AKT is found to be a consequence of the reduced expression of several inhibitors of PP2A, the major phosphatase of AKT, with CIP2A being the most prominent. To show that CIP2A loss is obligatory for decidualization, we performed this ATAC-seq analysis. Persistent CIP2A expression impairs the chromatin accesibility remodeling during decidualization.
2023-02-06 | GSE224212 | GEO
Project description:Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific function of these pathways in AML is unclear. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model of AML harboring Mll-AF9 and NRASG12V. We found that NRASG12V enforced leukemia self-renewal gene expression signatures and was required to maintain an MLL-AF9 and MYB-dependent gene expression program. In a multiplexed analysis of RAS-dependent signaling intermediates, the leukemia stem cell compartment was preferentially sensitive to RAS withdrawal. Use of RAS-pathway inhibitors showed that NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Primary NRASG12V-Mll-AF9 AML cells were treated in vitro for 24 hours with Ras-pathway inhibitors. RNA was extracted from these cells and submitted for RNA sequencing.
2014-11-16 | E-GEOD-49087 | biostudies-arrayexpress
Project description:Cancerous inhibitor of PP2A (CIP2A) Constrains Th17 Differentiation by Modulating STAT3 Signaling
| PRJNA484395 | ENA
Project description:Identification of ovarian cancer (OvCa) patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22 % of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels. Further, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient OvCa cells, we identified reactive oxygen species inducer APR-246, tested previously in OvCa clinical trials. Consistent with CIP2A-deficient OvCa subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse OvCa tumors. Nevertheless, CIP2A null OvCa tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the OvCa cells to APR-246 by inhibition of NF-kB activity. Accordingly, combination of APR-246 and NF-kB inhibitor compounds strongly synergized in killing of CIP2A positive OvCa cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient OvCa tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
2022-02-02 | GSE195984 | GEO
Project description:The generation of optimal immune response requires combined activation of both T- and B-cells. Here, we demonstrate that the cancerous inhibitor of protein phosphatase 2A (CIP2A) is a novel factor that governs activation of both T- and B-cells in vivo. Upon ovalbumin challenge, CIP2A-deficient (CIP2AHOZ) mice show impaired immune response. Furthermore, CIP2AHOZ mice had impaired clearance of Listeria Monocytogenesis (L.m.) infection, combined with decreased numbers of CD8+ T-cells and IFN-? secretion. In an ovalbumin model of allergic asthma, CIP2AHOZ B-cells were impaired in IgE and IgG secretion, despite of normal Th2 differentiation and unaffected numbers of inflammatory cells or cytokines in bronchoalveolar lavage. Importantly, the cell-autonomous effect of CIP2A deficiency for both T- and B-cell activation was confirmed by in vitro assays. During the T-cell activation CIP2A, was shown to promote expression of ETS-1, whereas in B-cells CIP2A loss resulted in inhibition of MYC-mediated gene expression. Together these results identify CIP2A as a novel cell-autonomous regulator governing both T- and B-cell activation in vivo. They also identify CIP2AHOZ as a novel murine model for investigation of impaired immune response and allergic asthma. Total RNA obtained from 4 male mutant mice was compared to 4 wild type controls.
2015-06-10 | E-GEOD-56401 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) has a bad prognosis, a fast progression and is difficult to treat, highlighting the need for new therapeutic targets. Aggressive tumors mostly show Epithelial-to-Mesenchymal Transition (EMT). Protein phosphatase type 2A (PP2A) plays a central role in processes of cell survival and proliferation, but the link with EMT and tumor progression is largely unknown. Therefore, we examined expression of a PP2A gene set in five datasets of human PDAC and their association with an aggressive phenotype. Two datasets included PDAC tumor samples and normal pancreatic tissue. In two other datasets, the samples could be classified into clinical/molecular subtypes of EMT-high/aggressive and EMT-low/moderate PDAC. Spearman correlation, hierarchical clustering and ROC-analysis were performed. EMT was also quantified using weighted expression of 8 marker genes. In each study we observed that, compared to normal tissue, (advanced) tumor stage positively and significantly correlated with EMT. EMT-high PDAC showed suppression of PPP2R1B and PPP2R2D expression and upregulation of PPP2R3C, PPP2R5E, STRN, STRN3 and PPP2R2A. A strong link was further found for upregulation of endogenous inhibitors of PP2A (KIAA1524/CIP2A, ARPP19, TIPRL and PPME1) with advanced PDAC. ROC-curve indicates that high expression of PP2A-inhibitors are predictors of aggressive PDAC. This was further investigated in a cell line model of Panc-1 cells made resistant to the PP2A-inhibitor Okadaic acid. Gene expression was determined in cells exposed for 24 hours and resistant cells. In summary, we demonstrate an important association of PP2A inhibition with EMT in advanced human pancreatic cancer. We then performed gene expression profiling analysis using data obtained from RNA-seq of 3 different cells.
2023-05-16 | GSE216036 | GEO
Project description:The purpose is to study the transcriptional changes in basal like breast cancer cell line HCC38 on depletion of CIP2A. We have used 3 unique siRNA sequences of CIP2A and 3 control samples (Mock and 2 unique non-targeting sequences) for the RNA Seq. We identified differentially expressed genes in CIP2A knockdown conditions compared to the control samples and identified pathways regulated by CIP2A in this cell line using GSEA.
2021-04-27 | GSE173302 | GEO
Project description:RNA seq on primary pancreatic cancer (KPPC;Col1pdxKO cancer-collagen1 knockout) cells growing on collagen 1 homotrimers and heterotrimers. In this study, we identify that pancreatic cancer cells produce a unique Collagen1 homotrimer variant, in contrast to the Collagen1 heterotrimer produced by normal cells (such as fibroblasts). The variant forms of Collagen1 (homotrimer and heterotrimer) have distinct effects on cancer cell behaviors. We culture the pancreatic cancer cells on purified Collagen1 homotrimer and heterotrimer (as well as vehicle control) and examine the global changes of gene expression profile in cancer cells by variant Collagen1 subtypes.
2022-05-21 | GSE131666 | GEO
Project description:The purpose is to study DMBA-induced transcriptome in WT and in Cip2a-/- mouse mammary gland tissues. We identified differentially expressed genes in DMBA-induced mammary gland in WT vs. Cip2a-/- mouse mammary glands.
2021-04-28 | GSE173405 | GEO