The PP2A subunit PR130 is a key regulator of cell development and oncogenic transformation

Dzulko, Melanie; Pons, Miriam; Henke, Andreas; Schneider, Günter; Krämer, Oliver

doi:10.1016/j.bbcan.2020.188453

Cited by 25 publications

(31 citation statements)

References 124 publications

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“…BAD plays a key role in mitochondria-dependent apoptosis, and its inactivation contributes to the development of rheumatoid arthritis by conferring apoptosis resistance in synovial sub lining macrophages [ 58 ]. PPP2R3A , a major serine/threonine phosphatase, is involved in a variety of cellular processes, including cell apoptosis, proliferation, DNA repair, and autophagy [ 59 ], and its knockdown inhibits the proliferation, migration, and invasion of hepatoma carcinoma cells [ 60 ]. CPT1B and ACACB are genes related to fatty acid oxidation [ 61 ] and are associated with obesity and diabetes.…”

Section: Discussionmentioning

confidence: 99%

Chitosan oligosaccharides packaged into rat adipose mesenchymal stem cells-derived extracellular vesicles facilitating cartilage injury repair and alleviating osteoarthritis

Liu

et al. 2021

J Nanobiotechnol

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Objectives This study aimed to investigate the roles of adipose mesenchymal stem cell (AMSC)-derived extracellular vesicles (EVs) binding with chitosan oligosaccharides (COS) in cartilage injury, as well as the related mechanisms. Results IL-1β treatment significantly inhibited the viability and migration of chondrocytes and enhanced cell apoptosis (P < 0.05), while chitosan oligosaccharides and extracellular vesicles-chitosan oligosaccharide conjugates (EVs-COS/EVs-COS conjugates) reversed the changes induced by IL-1β (P < 0.05), and the effects of extracellular vesicles-chitosan oligosaccharide conjugates were better than those of chitosan oligosaccharides (P < 0.05). After cartilage damage, IL-1β, OPN, and p53 were significantly upregulated, COL1A1, COL2A1, OCN, RUNX2, p-Akt/Akt, PI3K, c-Myc, and Bcl2 were markedly downregulated, and extracellular vesicles-chitosan oligosaccharide conjugates reversed the expression induced by cartilage injury. Through sequencing, 760 differentially expressed genes (DEGs) clustered into four expression patterns were associated with negative regulation of the canonical Wnt, PI3K-Akt, AMPK, and MAPK signaling pathways. Conclusion Extracellular vesicles-chitosan oligosaccharide conjugates may serve as a new cell-free biomaterial to facilitate cartilage injury repair and improve osteoarthritis. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Chitosan oligosaccharides packaged into rat adipose mesenchymal stem cells-derived extracellular vesicles facilitating cartilage injury repair and alleviating osteoarthritis

Liu

et al. 2021

J Nanobiotechnol

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“…Such differences in the dependency on STAT5 could rely on the different modes of drug actions. While hydroxyurea depletes the dNTP pool and stalls DNA synthesis, without a direct effect on DNA [4][5][6][7], cytarabine is metabolized and becomes incorporated into nascent DNA [56]. Further work is required to delineate the drug-induced DNA damage and repair pathways that STAT5 regulates.…”

Section: Discussionmentioning

confidence: 99%

“…Chemotherapeutics eliminate transformed cells through the induction of replication stress and DNA damage [1][2][3]. Hydroxyurea is used as cytoreductive therapy for leukemic disorders and brain tumors [4][5][6][7]. This drug specifically inhibits ribonucleotide reductase (RNR) and thereby depletes the cellular dNTP pool [8].…”

Section: Introductionmentioning

confidence: 99%

“…Chronic myeloid leukemia (CML) cells that are driven by the tyrosine kinase BCR-ABL1 (encoded by the reciprocal chromosomal translocation t(9;22)) [12,13] display particular robustness to apoptosis upon dNTP depletion by hydroxyurea [11]. Despite the long-standing use of hydroxyurea in the clinic [4][5][6][7], molecular details on specific signaling pathways that determine whether leukemic cells are responsive or resistant to pro-apoptotic effects of this drug are still to be identified. The modulation of such mechanisms in hydroxyurea-treated cells could deliver novel and improved treatment options.…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition

Pons

Zeyn

Zahn

et al. 2021

Cancers

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The ribonucleotide reductase inhibitor hydroxyurea suppresses de novo dNTP synthesis and attenuates the hyperproliferation of leukemic blasts. Mechanisms that determine whether cells undergo apoptosis in response to hydroxyurea are ill-defined. We used unbiased proteomics to uncover which pathways control the transition of the hydroxyurea-induced replication stress into an apoptotic program in chronic and acute myeloid leukemia cells. We noted a decrease in the serine/threonine kinase RAF1/c-RAF in cells that undergo apoptosis in response to clinically relevant doses of hydroxyurea. Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea. We further disclose that pharmacological inhibition of the RAF downstream target BCL-XL with the drug navitoclax and RNAi combine favorably with hydroxyurea against leukemic cells. BCR-ABL1 and hyperactive FLT3 are tyrosine kinases that causally contribute to the development of leukemia and induce RAF1 and BCL-XL. Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations.

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“…Various reports have shown that PP2A induces brosis through the WNT signaling pathway [26], PI3K/AKT signaling pathway, NFκB signaling pathway, calcium ion-related signaling pathway [27], p53 signaling pathway [28], etc (Figure 6A). To further explore the mechanism by which PPP2R3A causes pulmonary brosis, we rst investigated whether PPP2R3A causes pulmonary brosis through a mechanism involving calcium overload (Figure S7A and B).…”

Section: Ppp2r3a Promotes Pulmonary Brosis Via the P53 Pathwaymentioning

confidence: 99%

PPP2R3A Affects the Function and Mechanism of Heterogeneous Fibroblasts in Pulmonary Fibrosis

Shi¹,

Yang²,

Luo³

et al. 2021

Preprint

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Background: Fibroblasts have important roles in the synthesis and remodeling of extracellular matrix (ECM) proteins during pulmonary fibrosis. However, the spatiotemporal distribution of heterogeneous fibroblasts during disease progression remains unknown. Methods: Physiological saline and silica were used to generate a chronic pulmonary fibrosis model in mice, and single-cell sequencing, spatial transcriptome sequencing, real-time fluorescent quantitative PCR, immunohistochemistry and immunofluorescence were performed to identify fibroblast subtypes. Small interfering RNA was used to specifically knockdown the target protein, and western blotting, bromodeoxyuridine (BrdU), Cell Counting Kit-8 (CCK-8) and wound healing assays were used to detect the role of GREM1/PPP2R3A in a newly identified fibroblast subtype. Results: Fibroblasts of the new subtype were mainly located in the lesion area and coexpressed inflammation- and proliferation-related genes; they were termed inflammatory-proliferation fibroblasts. Grem1 was the most highly expressed gene in this subtype, as confirmed in HPF-a cells after TGF-β1 treatment. We characterized the downstream mechanism of GREM1/PPP2R3A: these factors mediated the increases in cell viability, proliferation and migration induced by TGF-β1 in fibroblasts. Conclusion: This new subtype of inflammatory, proliferative fibroblasts plays a pivotal role during pulmonary fibrosis, and PPP2R3A, as a downstream regulatory target of GREM1, is involved in pulmonary fibrosis, providing new insights for the prevention and treatment of silicosis.

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The PP2A subunit PR130 is a key regulator of cell development and oncogenic transformation

Cited by 25 publications

References 124 publications

Chitosan oligosaccharides packaged into rat adipose mesenchymal stem cells-derived extracellular vesicles facilitating cartilage injury repair and alleviating osteoarthritis

Chitosan oligosaccharides packaged into rat adipose mesenchymal stem cells-derived extracellular vesicles facilitating cartilage injury repair and alleviating osteoarthritis

Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition

PPP2R3A Affects the Function and Mechanism of Heterogeneous Fibroblasts in Pulmonary Fibrosis

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