A Signaling Crosstalk between BMP9 and HGF/c-Met Regulates Mouse Adult Liver Progenitor Cell Survival

During chronic liver disease, hepatic progenitor cells (HPC, oval cells in rodents) become activated, proliferate, and differentiate into cholangiocytes and/or hepatocytes contributing to the final outcome of the regenerative process in a context-dependent fashion. Here, we analyze the crosstalk between the hepatocyte growth factor (HGF)/c-Met signaling axis, key for liver regeneration, and bone morphogenetic protein (BMP)9, a BMP family ligand that has emerged as a critical regulator of liver pathology. Our results show that HGF/c-Met signaling blocks BMP9-mediated apoptotic cell death, while it potentiates small mothers against decapentaplegic (SMAD)1 signaling triggered by BMP9 in oval cells. Interestingly, HGF-induced overactivation of SMAD1, -5, -8 requires the upregulation of TGF-β type receptor activin receptor-like kinase (ALK)1, and both ALK1 and SMAD1 are required for the counteracting effect of HGF on BMP9 apoptotic activity. On the other hand, we also prove that BMP9 triggers the activation of p38MAPK in oval cells, which drives BMP9-apoptotic cell death. Therefore, our data support a model in which BMP9 and HGF/c-Met signaling axes establish a signaling crosstalk via ALK1 that modulates the balance between the two pathways with opposing activities, SMAD1 (pro-survival) and p38 mitogen-activated protein kinases (p38MAPK; pro-apoptotic), which determines oval cell fate. These data help delineate the complex signaling network established during chronic liver injury and its impact on the oval cell regenerative response.

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Presenilin-1 regulates neuronal differentiation during neurogenesis

Development ◽

10.1242/dev.127.12.2593 ◽

2000 ◽

Vol 127 (12) ◽

pp. 2593-2606 ◽

Cited By ~ 1

Author(s):

M. Handler ◽

X. Yang ◽

J. Shen

Keyword(s):

Cell Death ◽

Progenitor Cells ◽

Neuronal Differentiation ◽

Cell Fate ◽

Neural Progenitor Cells ◽

Apoptotic Cell ◽

Ventricular Zone ◽

Neural Progenitor ◽

Apoptotic Cell Death ◽

Presenilin 1

Mutations in Presenilin-1 (PS1) are a major cause of familial Alzheimer's disease. Our previous studies showed that PS1 is required for murine neural development. Here we report that lack of PS1 leads to premature differentiation of neural progenitor cells, indicating a role for PS1 in a cell fate decision between postmitotic neurons and neural progenitor cells. Neural proliferation and apoptotic cell death during neurogenesis are unaltered in PS1(−/−) mice, suggesting that the reduction in the neural progenitor cells observed in the PS1(−/−) brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In addition, the premature neuronal differentiation in the PS1(−/−) brain is associated with aberrant neuronal migration and disorganization of the laminar architecture of the developing cerebral hemisphere. In the ventricular zone of PS1(−/−) mice, expression of the Notch1 downstream effector gene Hes5 is reduced and expression of the Notch1 ligand Dll1 is elevated, whereas expression of Notch1 is unchanged. The level of Dll1 transcripts is also increased in the presomitic mesoderm of PS1(−/−) embryos, while the level of Notch1 transcripts is unchanged, in contrast to a previous report (Wong et al., 1997, Nature 387, 288–292). These results provide direct evidence that PS1 controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis.

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Klotho modulates ER-mediated signaling crosstalk between prosurvival autophagy and apoptotic cell death during LPS challenge

APOPTOSIS ◽

10.1007/s10495-018-1496-1 ◽

2018 ◽

Vol 24 (1-2) ◽

pp. 95-107 ◽

Cited By ~ 7

Author(s):

Jennifer Mytych ◽

Przemyslaw Solek ◽

Marek Koziorowski

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Signaling Crosstalk ◽

Lps Challenge

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Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential

Cancers ◽

10.3390/cancers14010076 ◽

2021 ◽

Vol 14 (1) ◽

pp. 76

Author(s):

Giulia Greco ◽

Michael Schnekenburger ◽

Elena Catanzaro ◽

Eleonora Turrini ◽

Fabio Ferrini ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Leukemia Cell ◽

Kinase Domain ◽

Apoptotic Cell Death ◽

Dependent Manner ◽

Interacting Protein ◽

Leukemia Cell Lines ◽

Cell Death Mechanisms ◽

Apoptotic Activity

In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities.

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The long noncoding RNA of RMRP is downregulated by PERK, which induces apoptosis in hepatocellular carcinoma cells

Scientific Reports ◽

10.1038/s41598-021-86592-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atsushi Yukimoto ◽

Takao Watanabe ◽

Kotaro Sunago ◽

Yoshiko Nakamura ◽

Takaaki Tanaka ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Transcriptome Analysis ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Chronic Liver ◽

Mitochondrial Rna

AbstractEndoplasmic reticulum (ER) stress plays an important role in hepatocyte degeneration, especially in patients with chronic liver injury. Protein kinase R-like endoplasmic reticulum kinase (PERK) is a key molecule in ER stress. PERK may contribute to apoptotic cell death in HCC, however the details of the mechanism are not clear. In this study, we identified PERK-associated molecules using transcriptome analysis. We modulated PERK expression using a plasmid, tunicamycin and siRNA against PERK, and then confirmed the target gene expression with real-time PCR and Northern blotting. We further analyzed the apoptotic function. Transcriptome analysis revealed that expression of the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), which is a long noncoding RNA, was strongly correlated with the function of PERK. The expression of RMRP was correlated with the expression of PERK in experiments with the siRNA and PERK plasmid in both HCC cell lines and human HCC tissue. Furthermore, RMRP downregulation induced apoptotic cell death. RMRP is downregulated by PERK, which induces apoptosis in HCC. RMRP could be a new therapeutic target to regulate HCC in patients with chronic liver diseases associated with ER stress.

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Chronic Lymphocytic Leukemia Apoptotic Cell Death Induced by Glucocorticoids Is Mediated by BIM and GILZ and Can Be Predicted by FKBP5 Basal Expression Levels.

Blood ◽

10.1182/blood.v114.22.1236.1236 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1236-1236

Author(s):

Maria Joao Baptista ◽

Ana Muntañola ◽

Carles Codony ◽

Eva Calpe ◽

Eva Fernandez ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Lymphocytic Leukemia ◽

Mrna Levels ◽

Rt Pcr ◽

Genome Wide ◽

Apoptotic Effect ◽

Apoptotic Activity ◽

Induced Apoptosis

Abstract Abstract 1236 Poster Board I-258 Glucocorticoids (GC) apoptotic effect in chronic lymphocytic leukemia (CLL) cells is known for many years. However, in CLL their use is often confined to their immunosuppressive activity in order to control autoimmune phenomena or as palliation. The fact that GC, particularly dexamethasone (DEX), can overcome p53 mediated resistance to therapy has renewed the interest in the use of GC as therapeutic agents in CLL. GC apoptotic induced cell death mechanism seems to depend on cell type and few studies were performed in CLL. GC increasing importance as apoptotic agent in CLL prompted us to analyze DEX apoptotic activity in CLL cells in order to clarify GC apoptotic mechanisms. For this, peripheral blood samples from 45 patients with CLL were selected for in vitro studies. Patients were analyzed for IGHV mutational status and ZAP-70 expression. Tumour cells were cultured over 24 hours with DEX at 13.25uM and viability was then determined by surface annexin V binding and propidium iodide (PI) staining flow cytometry analysis. To determine early apoptotic signal onset, BIM mRNA GC induced expression was quantified at different time points by quantitative RT-PCR. Genome-wide expression profile of CLL cells was done to discriminate genes involved in DEX apoptotic action. After 24 hours of exposure to therapeutic concentrations of DEX, cell viability was higher in mutated cases (M-CLL) than in unmutated IGHV cases (UM-CLL) (85.6% vs 69.5% in mean, respectively; p=0.000). mRNA BIM expression after 24 hours of treatment with DEX correlated with induced apoptotic cell death (R=0.496; p=0.000). As a consequence, UM-CLL had higher levels of induced mRNA levels of BIM than M-CLL cases (p=0.036). Time course experiments have shown that at 6h after DEX treatment BIM mRNA levels were induced 3 times without influence on cell viability. Genome-wide expression analysis of 12 CLL cases (7 UM-CLL, 5 M-CLL) was done after 6 hours of DEX treatment and was compared to the baseline gene expression. In both groups many genes were up and down regulated by DEX (UM-CLL 3359 genes and M-CLL 1008 genes, p adjusted < 0.01). Analysis of genes involved in the GC pathway revealed that basal mRNA levels of FKBP5, a protein essential to maintain the GC receptor (GR) complex suitable for GC binding, was more expressed in UM-CLL than in M-CLL cases (1.85 times, p= 0.027). Analysis by quantitative RT-PCR performed in 45 CLL patients to validate micro-array data confirmed that at baseline, FKPB5 expression was higher in UM-CLL than M-CLL (0.97 vs. 0.74 arbitrary units, respectively; p=0.042). The same was observed at protein level, WB analysis of FKBP5 basal levels showed that UM-CLL cases expressed more this protein than M-CLL (Fig. 1). In addition to that, genome-wide analysis revealed that GILZ, a glucocorticoid-induced leucine zipper, was differently induced by DEX in the studied groups. GILZ mRNA was less induced in M-CLL cases than in UM-CLL cases (difference fold change=0.52, p=0.0005). These results were also confirmed in 45 CLL cases by quantitative RT-PCR: in M-CLL, GILZ was induced 3.67 times whilst it was induced 5.62 times in UM-CLL cases (p=0.0001). In conclusion, treatment with GC induces more apoptotic cell death in UM-CLL than in M-CLL. As a downstream effect, BIM expression after GC exposure correlates with GC-induced apoptosis. Moreover, GC apoptotic effect in CLL is the result of several cell pathways imbalance as revealed by gene expression analysis. GILZ induction was proved to be necessary for DEX induced apoptosis in other cell types like multiple myeloma cell lines. In CLL, GILZ differential induction was observed at different degrees in GC-responders and non-responders. Finally, FKBP5 expression, upstream effecter of the GC pathway, correlated with cellular effect of GC and can be used to predict GC apoptotic activity in CLL cases. Figure 1 WB analysis of FKBP5 expression in CLL cells. Figure 1. WB analysis of FKBP5 expression in CLL cells. Disclosures No relevant conflicts of interest to declare.

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