Modeling cell-to-cell stochastic variability in intrinsic apoptosis pathway

2012 ◽  
Author(s):  
Hsu Kiang Ooi ◽  
Lan Ma
Keyword(s):  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

scholarly journals Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Christopher Platen ◽  
Stephan Dreschers ◽  
Jessica Wappler ◽  
Andreas Ludwig ◽  
Stefan Düsterhöft ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Infections ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Intrinsic Apoptosis ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-XL, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-XL and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.

Alantolactone induces apoptosis in THP‐1 cells through STAT3, survivin inhibition, and intrinsic apoptosis pathway

2020 ◽  
Author(s):  
Bashir Ahmad ◽  
Yaser Gamallat ◽  
Pengyu Su ◽  
Akbar Husain ◽  
Ata Ur Rehman ◽  
...  
Keyword(s):  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

scholarly journals Cell death following the loss of ADAR1 mediated A-to-I RNA editing is not effected by the intrinsic apoptosis pathway

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Carl R. Walkley ◽  
Benjamin T. Kile
Keyword(s):  
Cell Death ◽  
Rna Editing ◽  
Rna Structure ◽  
Fetal Liver ◽  
Loss Of Function ◽  
Intrinsic Apoptosis ◽  
Triple Mutant ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

AbstractModifications of RNA, collectively termed as the epitranscriptome, are widespread, evolutionarily conserved and contribute to gene regulation and protein diversity in healthy and disease states. There are >160 RNA modifications described, greatly exceeding the number of modifications to DNA. Of these, adenosine-to-inosine (A-to-I) RNA editing is one of the most common. There are tens of thousands of A-to-I editing sites in mouse, and millions in humans. Upon translation or sequencing an inosine base is decoded as guanosine, leading to A-to-G mismatches between the RNA and DNA. Inosine has different base pairing properties to adenosine and as a result editing not only alters the RNA code but can also change the RNA structure. In mammals A-to-I editing is performed by ADAR1 and ADAR2. A feature of murine loss of function ADAR1 alleles is cell death and a failure to survive embryogenesis. Adar1−/− and editing deficient (Adar1E861A/E861A) mice die between E11.75–13.5 of failed hematopoiesis. Strikingly this phenotype is rescued by the deletion of the cytosolic dsRNA sensor MDA5 or its downstream adaptor MAVS, a mechanism conserved in human and mouse. Current literature indicates that the loss of ADAR1 leads to cell death via apoptosis, yet this has not been genetically established. We report that blockade of the intrinsic (mitochondrial) apoptosis pathway, through the loss of both BAK and BAX, does not rescue or modify the cellular phenotype of the fetal liver or extend the lifespan of ADAR1 editing deficient embryos. We had anticipated that the loss of BAK and BAX would rescue, or at least significantly extend, the gestational viability of Adar1E861A/E861A embryos. However, the triple mutant Adar1E861A/E861ABak−/−Bax−/− embryos that were recovered at E13.5 were indistinguishable from the Adar1E861A/E861A embryos with BAK and BAX. The results indicate that cell death processes not requiring the intrinsic apoptosis pathway are triggered by MDA5 following the loss of ADAR1.

scholarly journals High expression of anti-apoptotic genes in grade I and II meningiomas

2017 ◽  
Vol 75 (4) ◽  
pp. 209-215 ◽  
Author(s):  
Daniela Pretti da Cunha Tirapelli ◽  
Sarah Bomfim Menezes ◽  
Indira Maynart Franco ◽  
Isis Lacrose Lustosa ◽  
Andressa Romualdo Rodrigues ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Control Group ◽  
Intrinsic Apoptosis ◽  
Extrinsic Pathway ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
Apoptosis Pathways ◽  
Genetic Mechanisms ◽  
Apoptotic Genes ◽  
Low Expression

ABSTRACT One of the different genetic mechanisms involved in the carcinogenesis of meningiomas is influenced by interactions between proteins that induce and inhibit apoptosis. Objective To evaluate the expression of c-FLIP, XIAP, Bcl-2, caspase 3, 8 and 9, cytochrome c, APAF 1 and Smac/DIABLO genes related to apoptosis pathways. Methods The gene expression was evaluated in 30 meningiomas (WHO grades I and II) and in 10 normal samples (from arachnoid tissue) through PCR-RT. Results The results showed higher expression of anti-apoptotic genes in meningiomas when compared to the control group, which had a low expression of pro-apoptotic genes. Conclusion There is a possible block in the activation of caspases through the intrinsic apoptosis pathway in meningiomas. c-FLIP modulates caspase 8 and, by inhibiting its activation due to the lack of connection with the receiver, there is a block to the FAS activation of apoptosis by its extrinsic pathway.

Megakaryocytes Possess a Functional Intrinsic Apoptosis Pathway That Must Be Restrained In Order to Survive and Produce Platelets

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 550-550
Author(s):  
Emma C Josefsson ◽  
Chloé James ◽  
Katya J Henley ◽  
Marlyse A Debrincat ◽  
Kelly L Rogers ◽  
...  
Keyword(s):  
Life Span ◽  
Intrinsic Apoptosis ◽  
Intrinsic Pathway ◽  
Apoptosis Pathway ◽  
Platelet Production ◽  
Apoptotic Death ◽  
Intrinsic Apoptosis Pathway ◽  
Bh3 Mimetic ◽  
Platelet Formation

Abstract Abstract 550 It is widely held that megakaryocytes undergo a specialized form of apoptosis in order to shed platelets. Conversely, it is also believed that a range of insults including chemotherapeutic agents, autoantibodies and viruses, cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. However, the apoptotic pathways that megakaryocytes possess, and the role they play in survival and platelet production are ill-defined. We recently demonstrated that platelets contain a classical intrinsic mitochondrial apoptosis pathway that regulates their life span in vivo. The key components of this pathway are the Bcl-2 family pro-survival protein Bcl-xL, and pro-death Bak and Bax. Deletion of Bak and Bax—the gatekeepers of the intrinsic pathway—blocks platelet apoptosis in response to genetic mutation or pharmacological insult, and significantly extends circulating platelet life span. To elucidate the role of the intrinsic apoptosis pathway in megakaryocytes, we generated both hematopoietic- and megakaryocyte lineage-specific deletions of Bak and Bax in mice. Surprisingly, we found that the ability of Bak−/−Bax−/− animals to produce platelets, both at steady state and under conditions of thrombopoietic stress, was unperturbed. Megakaryocyte numbers, morphology and ploidy were normal. Bak−/−Bax−/− megakaryocytes cultured in vitro showed no impairment of pro-platelet formation. Thus, classical intrinsic apoptosis is not required by megakaryocytes for the process of platelet shedding. Given that in platelets, Bak and Bax must be kept in check to maintain survival, we reasoned that the same might be true of megakaryocytes. If so, then it would be expected that one or more members of the Bcl-2 family of pro-survival proteins restrain Bak and Bax. Since Bcl-xL fulfills this role in platelets, we generated mice lacking Bcl-xL in the megakaryocyte lineage. Platelet counts in Bcl-xPf4CΔ/Pf4CΔ animals were approximately 2% of those observed in Bcl-xfl/fl littermates. Platelet life span was reduced to 5 hours, versus 5 days in controls, underscoring the requirement for Bcl-xL in mediating platelet survival. In addition, reticulated platelet analyses combined with mathematical modeling suggested that Bcl-xPf4CΔ/Pf4CΔ mice had an underlying platelet production defect. Further examination revealed that megakaryocyte numbers were significantly increased in both the bone marrow and spleen of Bcl-xPf4CΔ/Pf4CΔ animals relative to Bcl-xfl/fl controls. Megakaryocyte progenitor numbers were doubled, and serum TPO levels were dramatically reduced, indicating a megakaryocyte compartment under considerable thrombopoietic stress. In vitro cultures confirmed that Bcl-xPf4CΔ/Pf4CΔ megakaryocytes were able to develop and mature. Strikingly, however, at the point of pro-platelet formation, they underwent an abortive attempt to generate extensions and died. Death was accompanied by a dramatic increase in apoptotic effector caspase activity. This suggested that, like platelets, megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained in order to survive, and that Bcl-xL is the factor that does so during pro-platelet formation and platelet shedding. To establish whether Bak and Bax can mediate megakaryocyte death, we examined the effect on mature wild type megakaryocytes of three pharmacological agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and a BH3 mimetic that inhibits Bcl-xL, Bcl-2 and Bcl-w. All three triggered mitochondrial damage, caspase activation and cell death. Remarkably, genetic deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and the BH3 mimetic, but not staurosporine. Our results demonstrate that megakaryocytes can undergo classical Bak- and Bax-mediated apoptotic death. They do not activate the intrinsic pathway to facilitate platelet shedding, rather, the opposite is true: they must restrain it in order to survive and generate platelets. These findings offer a potential mechanism for the death of megakaryocytes in response to insults such as cancer chemotherapy. They also suggest that additional megakaryocyte cell death pathways remain to be elucidated. Disclosures: Roberts: Abbott: Research Funding.

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