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MDAMB-231 Fusion Lumos, LC-MSMS

ABSTRACT: The protein phosphatase 2A (PP2A) heterotrimer PP2A-B56A is a human tumor suppressor. However, the molecular mechanisms inhibiting PP2A-B56A in cancer are poorly understood. Here, we report Phosphoproteomics study of single point mutation of CIP2A(K21A) in triple negative breast cancer cell line (MDA-MB-231).

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

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			Action	DRS
	210812_IMAC_Pool1.raw	Raw
	210812_IMAC_Pool2.raw	Raw
	210820_Sample_1.raw	Raw
	210820_Sample_2.raw	Raw
	210820_Sample_3.raw	Raw

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Structural mechanism for inhibition of PP2A-B56 and oncogenicity by CIP2A

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

cAMP/PKA signaling promotes AKT deactivation via reducing CIP2A expression, thereby facilitating decidualization

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.

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NRASG12V mediates self renewal in AML [RNA-Seq]

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Cancerous inhibitor of PP2A (CIP2A) Constrains Th17 Differentiation by Modulating STAT3 Signaling

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Ovarian cancers with low CIP2A tumor expression constitute an APR-246 sensitive disease subtype

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.

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Effect of Okadaic Acid on gene expression in human pancreatic cells

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.

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Cancerous inhibitor of Protein Phosphatase 2A is a novel cell-autonomous regulator governing both T-and B-cell activation in vivo

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