scholarly journals Caspase-8, RIPK1, and RIPK3 Coordinately Regulate Retinoic Acid-Induced Cell Differentiation and Necroptosis

2017 ◽  
Author(s):  
Masataka Someda ◽  
Shunsuke Kuroki ◽  
Makoto Tachibana ◽  
Shin Yonehara
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
Es Cells ◽  
Death Receptor ◽  
Binding Activity ◽  
Embryoid Bodies ◽  
Caspase 8 ◽  
Retinoic Acid Response Element

AbstractCaspase-8, which is essential for death receptor-mediated apoptosis, inhibits necroptosis by suppressing the function of RIPK1 and RIPK3 to activate MLKL. We show that knockdown of caspase-8 expression in embryoid bodies derived from ES cells markedly enhances retinoic acid (RA)-induced cell differentiation and necroptosis, both of which are dependent on Ripkl and Ripk3. RA treatment obviously enhanced the expression of RA-specific genes having a retinoic acid response element (RARE) to induce cell differentiation, and induced marked expression of RIPK1, RIPK3 and MLKL to stimulate necroptosis. Caspase-8 knockdown induced RA receptor (RAR) to form a complex with RIPK1 and RIPK3 in the nucleus, and RAR interacting with RIPK1 and RIPK3 showed much stronger binding activity to RARE than RAR without RIPK1 or RIPK3. In Caspase-8-deficient mouse embryos, expression of RA-specific genes was obviously enhanced. Thus, caspase-8, RIPK1, and RIPK3 regulate RA-induced cell differentiation and necroptosis both in vitro and in vivo.

scholarly journals Caspase-8, receptor-interacting protein kinase 1 (RIPK1), and RIPK3 regulate retinoic acid-induced cell differentiation and necroptosis

2019 ◽  
Vol 27 (5) ◽  
pp. 1539-1553 ◽  
Author(s):  
Masataka Someda ◽  
Shunsuke Kuroki ◽  
Hitoshi Miyachi ◽  
Makoto Tachibana ◽  
Shin Yonehara
Keyword(s):  
Retinoic Acid ◽  
Cell Differentiation ◽  
Protein Kinase ◽  
Target Genes ◽  
Es Cells ◽  
Embryoid Bodies ◽  
Embryonic Lethality ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Specific Target

Abstract Among caspase family members, Caspase-8 is unique, with associated critical activities to induce and suppress death receptor-mediated apoptosis and necroptosis, respectively. Caspase-8 inhibits necroptosis by suppressing the function of receptor-interacting protein kinase 1 (RIPK1 or RIP1) and RIPK3 to activate mixed lineage kinase domain-like (MLKL). Disruption of Caspase-8 expression causes embryonic lethality in mice, which is rescued by depletion of either Ripk3 or Mlkl, indicating that the embryonic lethality is caused by activation of necroptosis. Here, we show that knockdown of Caspase-8 expression in embryoid bodies derived from ES cells markedly enhances retinoic acid (RA)-induced cell differentiation and necroptosis, both of which are dependent on Ripk1 and Ripk3; however, the enhancement of RA-induced cell differentiation is independent of Mlkl and necrosome formation. RA treatment obviously enhanced the expression of RA-specific target genes having the retinoic acid response element (RARE) in their promoter regions to induce cell differentiation, and induced marked expression of RIPK1, RIPK3, and MLKL to stimulate necroptosis. Caspase-8 knockdown induced RIPK1 and RIPK3 to translocate into the nucleus and to form a complex with RA receptor (RAR), and RAR interacting with RIPK1 and RIPK3 showed much stronger binding activity to RARE than RAR without RIPK1 or RIPK3. In Caspase-8-deficient as well as Caspase-8- and Mlkl-deficient mouse embryos, the expression of RA-specific target genes was obviously enhanced. Thus, Caspase-8, RIPK1, and RIPK3 regulate RA-induced cell differentiation and necroptosis both in vitro and in vivo.

scholarly journals The Caspase 8 Inhibitor c-FLIPL Modulates T-Cell Receptor-Induced Proliferation but Not Activation-Induced Cell Death of Lymphocytes

2002 ◽  
Vol 22 (15) ◽  
pp. 5419-5433 ◽  
Author(s):  
Susanne M. A. Lens ◽  
Takao Kataoka ◽  
Karen A. Fortner ◽  
Antoine Tinel ◽  
Isabel Ferrero ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Receptor ◽  
Death Receptor ◽  
Cell Receptor ◽  
Caspase 8 ◽  
Activation Induced Cell Death

ABSTRACT The caspase 8 inhibitor c-FLIPL can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIPL in the T-cell compartment (c-FLIPL Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIPL Tg mice. In contrast, activation-induced cell death of T cells in c-FLIPL Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIPL Tg mice differed from Fas-deficient mice by showing no accumulation of B220+ CD4− CD8− T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIPL Tg mice. Thus, a major role of c-FLIPL in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.

Identification and Characterization of Hemoangiogenic Progenitors during Cynomolgus Monkey ES Cell Differentiation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3222-3222
Author(s):  
Katsutsugu Umeda ◽  
Toshio Heike ◽  
Momoko Yoshimoto ◽  
Mitsutaka Shiota ◽  
Feng Ma ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Es Cells ◽  
Close Association ◽  
Growth Factor Receptor ◽  
Intermediate Stage ◽  
Surface Markers ◽  
Es Cell ◽  
Cd34 Cells

Abstract Previous reports about the close association of development of hematopoietic (HCs) and endothelial cells (ECs) have suggested the presence of the hemangioblast, a putative common precursor of both lineage cells in mouse. The presence of putative ancestors is suggested by the fact that both HCs and ECs share common markers such as vascular endothelial growth factor receptor (VEGFR)-2, CD34, and CD31. The precise analysis about the relationship of HCs and ECs in human embryogenesis, however, remains unclear because of obstacle including the ethical restrictions on experiments using their embryo. To further understand the mechanisms that regulate the differentiation of HCs and ECs in humans, it is currently necessary to employ primate (human and monkey) ES cells. In this study, we identified the intermediate-stage cells with HC and EC differentiation potentials from nonhuman primate ES cells by coculture with OP9 stromal cells. Sequential FACS analysis demonstrated that during in vitro HC and EC differentiation, the expression of common surface markers such as CD34 and CD31 could first be detected, followed by the expression of lineage-specific markers (CD45, CD41 and VE-cadherin) in order. Sequential FACS and immunostaining analyses showed that both lineage developments concomitantly occurred, which were preceded by emergence of two hemoangiogenic progenitors, VEGFR-2high CD34− and VEGFR-2high CD34+ cells. While both VEGFR-2 high cells could differentiate into primitive and definitive HCs as well as ECs, VEGFR-2high CD34+ cells possessed higher hemoangiogenic potential than VEGFR-2high CD34− cells. In contrast, HC and EC production cluster was rare in the VEGFR-2low or − fractions. During HC and EC differentiation, most of VEGFR-2high cells first expressed CD34, and then diverged into both lineage cells at the VEGFR-2high CD34+ stage. We found that the VEGFR-2high cells can generate both HCs and ECs at the single cell level, which strongly supports the existence of hemangioblasts in primates. To our knowledge, this is the first time that hemangioblasts have been shown to be present during primate ES cell differentiation. Furthermore, differentiation pathway into HC and EC lineages can be defined by surface markers, which facilitates further investigations in vitro and in vivo.

scholarly journals Development of Mouse Embryonic Stem (ES) Cells: IV Differentiation to Mature T and B Lymphocytes after Implantation of Embryoid Bodies Into Nude Mice

1995 ◽  
Vol 4 (2) ◽  
pp. 79-84 ◽  
Author(s):  
Una Chen ◽  
Hoyan Mok
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nude Mice ◽  
Fetal Liver ◽  
Es Cells ◽  
Embryonic Stem ◽  
Embryoid Bodies ◽  
Lymphoid Cells

Mouse embryonic stem (ES) cells in culture can differentiate into late stages of many lineage-committed precursor cells. Under appropriate organ-culture conditions, ES cels differentiate into lymphoidlike cells at a stage equivalent to lymphoid cells found in fetal liver. These hematopoietic precursors are located in cup-shaped structures found in some embryoid bodies; we called such embryoid bodies “ES fetuses.” In this study, we have followed the maturation of hematopoietic cells after implantation of ES fetuses into nude mice for 3 weeks. ES-cell-derived lymphoid cells-pre-B cells, mature B cells, and mature T cells were found in all lymphoid organs. Interestingly, there was also an increase of T cells of host origin. Because native nude mouse lack thymus, these T cells might be educated by thymuslike epithelium generated from ES fetuses. Practical applications of this combinedin vitroandin vivosystem are discussed.

scholarly journals A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3097-3105 ◽  
Author(s):  
Brandon K. Hadland ◽  
Stacey S. Huppert ◽  
Jyotshnabala Kanungo ◽  
Yingzi Xue ◽  
Rulang Jiang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Fetal Liver ◽  
Es Cells ◽  
Es Cell ◽  
Chimeric Mice ◽  
Developmental Potential ◽  
Definitive Hematopoiesis

Abstract Notch1 is known to play a critical role in regulating fates in numerous cell types, including those of the hematopoietic lineage. Multiple defects exhibited by Notch1-deficient embryos confound the determination of Notch1 function in early hematopoietic development in vivo. To overcome this limitation, we examined the developmental potential of Notch1–/– embryonic stem (ES) cells by in vitro differentiation and by in vivo chimera analysis. Notch1 was found to affect primitive erythropoiesis differentially during ES cell differentiation and in vivo, and this result reflected an important difference in the regulation of Notch1 expression during ES cell differentiation relative to the developing mouse embryo. Notch1 was dispensable for the onset of definitive hematopoiesis both in vitro and in vivo in that Notch1–/– definitive progenitors could be detected in differentiating ES cells as well as in the yolk sac and early fetal liver of chimeric mice. Despite the fact that Notch1–/– cells can give rise to multiple types of definitive progenitors in early development, Notch1–/– cells failed to contribute to long-term definitive hematopoiesis past the early fetal liver stage in the context of a wild-type environment in chimeric mice. Thus, Notch1 is required, in a cell-autonomous manner, for the establishment of long-term, definitive hematopoietic stem cells (HSCs).

scholarly journals Generation of embryonic stem cell lines from mouse blastocysts developed in vivo and in vitro: relation to Oct-4 expression

Reproduction ◽  
2006 ◽  
Vol 132 (1) ◽  
pp. 59-66 ◽  
Author(s):  
S Tielens ◽  
B Verhasselt ◽  
J Liu ◽  
M Dhont ◽  
J Van Der Elst ◽  
...  
Keyword(s):  
Cell Lines ◽  
Inner Cell Mass ◽  
Es Cells ◽  
Cell Mass ◽  
Embryonic Stem ◽  
Embryoid Bodies ◽  
Differentiation Potential ◽  
Stem Cell Lines

Embryonic stem (ES) cells are the source of all embryonic germ layer tissues. Oct-4 is essential for their pluripotency. Sincein vitroculture may influence Oct-4 expression, we investigated to what extent blastocysts culturedin vitrofrom the zygote stage are capable of expressing Oct-4 and generating ES cell lines. We comparedin vivowithin vitroderived blastocysts from B6D2 mice with regard to Oct-4 expression in inner cell mass (ICM) outgrowths and blastocysts. ES cells were characterized by immunostaining for alkaline phosphatase (ALP), stage-specific embryonic antigen-1 (SSEA-1) and Oct-4. Embryoid bodies were made to evaluate the ES cells’ differentiation potential. ICM outgrowths were immunostained for Oct-4 after 6 days in culture. A quantitative real-time PCR assay was performed on individual blastocysts. Of thein vitroderived blastocysts, 17% gave rise to ES cells vs 38% of thein vivoblastocysts. Six-day old outgrowths fromin vivodeveloped blastocysts expressed Oct-4 in 55% of the cases vs 31% of thein vitroderived blastocysts. The amount of Oct-4 mRNA was significantly higher for freshly collectedin vivoblastocysts compared toin vitrocultured blastocysts.In vitrocultured mouse blastocysts retain the capacity to express Oct-4 and to generate ES cells, be it to a lower level thanin vivoblastocysts.

scholarly journals Induction of Pluripotency in Adult Equine Fibroblasts without c-MYC

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Khodadad Khodadadi ◽  
Huseyin Sumer ◽  
Maryam Pashaiasl ◽  
Susan Lim ◽  
Mark Williamson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Es Cells ◽  
Embryonic Stem ◽  
Histochemical Staining ◽  
Chromosome Count ◽  
Embryoid Bodies ◽  
Retroviral Transduction

Despite tremendous efforts on isolation of pluripotent equine embryonic stem (ES) cells, to date there are few reports about successful isolation of ESCs and no report ofin vivodifferentiation of this important companion species. We report the induction of pluripotency in adult equine fibroblasts via retroviral transduction with three transcription factors usingOCT4, SOX2, andKLF4in the absence of c-MYC. The cell lines were maintained beyond 27 passages (more than 11 months) and characterized. The equine iPS (EiPS) cells stained positive for alkaline phosphatase by histochemical staining and expressed OCT4, NANOG, SSEA1, and SSEA4. Gene expression analysis of the cells showed the expression ofOCT4, SOX2 NANOG, andSTAT3. The cell lines retained a euploid chromosome count of 64 after long-term culture cryopreservation. The EiPS demonstrated differentiation capacity for the three embryonic germ layers bothin vitroby embryoid bodies (EBs) formation andin vivoby teratoma formation. In conclusion, we report the derivation of iPS cells from equine adult fibroblasts and long-term maintenance using either of the three reprogramming factors.

scholarly journals Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma

2018 ◽  
Vol 19 (12) ◽  
pp. 3798 ◽  
Author(s):  
Giulia Fianco ◽  
Claudia Contadini ◽  
Alessandra Ferri ◽  
Claudia Cirotti ◽  
Venturina Stagni ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Cellular Systems ◽  
Caspase 8 ◽  
Cancer Resistance ◽  
Inhibitory Protein ◽  
Novel Target

Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.

scholarly journals In vitro and in vivo anti-cancer activity of silymarin on oral cancer

Tumor Biology ◽  
2018 ◽  
Vol 40 (5) ◽  
pp. 101042831877617 ◽  
Author(s):  
Dong-Hoon Won ◽  
Lee-Han Kim ◽  
Boonsil Jang ◽  
In-Hyoung Yang ◽  
Hye-Jeong Kwon ◽  
...  
Keyword(s):  
Oral Cancer ◽  
Apoptotic Cell ◽  
Death Receptor ◽  
Caspase 8 ◽  
Death Receptor 5 ◽  
Apoptosis Protein ◽  
Anti Cancer ◽  
Cancer Activity

Silymarin, a standardized extract from milk thistle fruits has been found to exhibit anti-cancer effects against various cancers. Here, we explored the anti-cancer activity of silymarin and its molecular target in human oral cancer in vitro and in vivo. Silymarin dose-dependently inhibited the proliferation of HSC-4 oral cancer cells and promoted caspase-dependent apoptosis. A human apoptosis protein array kit showed that death receptor 5 may be involved in silymarin-induced apoptosis, which was also shown through western blotting, immunocytochemistry, and reverse transcription-polymerase chain reaction. Silymarin increased cleaved caspase-8 and truncated Bid, leading to accumulation of cytochrome c. In addition, silymarin activated death receptor 5/caspase-8 to induce apoptotic cell death in two other oral cancer cell lines (YD15 and Ca9.22). Silymarin also suppressed tumor growth and volume without any hepatic or renal toxicity in vivo. Taken together, these results provide in vitro and in vivo evidence supporting the anti-cancer effect of silymarin and death receptor 5, and caspase-8 may be essential players in silymarin-mediated apoptosis in oral cancer.

scholarly journals Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins

2001 ◽  
Vol 155 (3) ◽  
pp. 459-470 ◽  
Author(s):  
Dwayne G. Stupack ◽  
Xose S. Puente ◽  
Souphaphone Boutsaboualoy ◽  
Chris M. Storgard ◽  
David A. Cheresh
Keyword(s):  
Three Dimensional ◽  
Death Receptor ◽  
Caspase 8 ◽  
Adherent Cells ◽  
Caspase Activity ◽  
Independent Manner ◽  
Integrin Antagonists ◽  
Per Se

Integrin-mediated adhesion promotes cell survival in vitro, whereas integrin antagonists induce apoptosis of adherent cells in vivo. Here, we demonstrate that cells adherent within a three-dimensional extracellular matrix undergo apoptosis due to expression of unligated integrins, the β subunit cytoplasmic domain, or its membrane proximal sequence KLLITIHDRKEF. Integrin-mediated death requires initiator, but not stress, caspase activity and is distinct from anoikis, which is caused by the loss of adhesion per se. Surprisingly, unligated integrin or β integrin tails recruit caspase-8 to the membrane, where it becomes activated in a death receptor–independent manner. Integrin ligation disrupts this integrin–caspase containing complex and increases survival, revealing an unexpected role for integrins in the regulation of apoptosis and tissue remodeling.

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