scholarly journals Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction

2006 ◽  
Vol 203 (13) ◽  
pp. 2939-2951 ◽  
Author(s):  
Miriam Erlacher ◽  
Verena Labi ◽  
Claudia Manzl ◽  
Günther Böck ◽  
Alexandar Tzankov ◽  
...  
Keyword(s):  
Cell Death ◽  
Physiological Role ◽  
B Cell Lymphoma ◽  
Apoptosis Induction ◽  
Induced Apoptosis ◽  
The Individual ◽  
Rate Limiting ◽  
Lymphatic Organs ◽  
Single Knockout

The physiological role of B cell lymphoma 2 (Bcl-2) homology 3–only proteins has been investigated in mice lacking the individual genes identifying rate-limiting roles for Bim (Bcl-2–interacting mediator of cell death) and Puma (p53–up-regulated modulator of apoptosis) in apoptosis induction. The loss of Bim protects lymphocytes from apoptosis induced by cytokine deprivation and deregulated Ca++ flux and interferes with the deletion of autoreactive lymphocytes and the shutdown of immune responses. In contrast, Puma is considered the key mediator of p53-induced apoptosis. To investigate the hypothesis that Bim and Puma have overlapping functions, we generated mice lacking both genes and found that bim−/−/puma−/− animals develop multiple postnatal defects that are not observed in the single knockout mice. Most strikingly, hyperplasia of lymphatic organs is comparable with that observed in mice overexpressing Bcl-2 in all hemopoietic cells exceeding the hyperplasia observed in bim−/− mice. Bim and Puma also have clearly overlapping functions in p53-dependent and -independent apoptosis. Their combined loss promotes spontaneous tumorigenesis, causing the malignancies observed in Bcl-2 transgenic mice, but does not exacerbate the autoimmunity observed in the absence of Bim.

Caspase-8 Determines Chemosensitivity of ALL Cells and Mediates Favorable Interactions of Cytotoxic Drugs,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3511-3511
Author(s):  
Harald Ehrhardt ◽  
Irmela Jeremias
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Epigenetic Silencing ◽  
Cytotoxic Drugs ◽  
Caspase 8 ◽  
Apoptosis Induction ◽  
Drug Induced ◽  
Induced Apoptosis

Abstract Abstract 3511 Sensitivity of tumor cells towards chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemo-sensitivity remain poorly understood. Here, we aimed at characterizing the role of Caspase-8 for chemo-sensitivity of B- and T-ALL cells. Several different drugs of routine anti-leukemia therapy were tested in vitro. All drugs that induced cell death also activated and cleaved Caspase-8. Caspase-8 was activated independently from extrinsic apoptosis signaling suggesting a downstream amplifier role of Caspase-8 upon drug-induced apoptosis in ALL cells. Most importantly, Asparaginase, Cyclophosphamide, Dexamethasone and Doxorubicin induced apoptosis in a Caspase-8 dependent manner as knockdown of Caspase-8 inhibited drug-induced apoptosis. Accordingly in primary ALL cells, the protein expression levels of Caspase-8 correlated with cell death sensitivity towards these cytotoxic drugs in vitro. In contrast, Cytarabin, Etoposid and others induced apoptosis via Caspase-8 independent signaling. Thus protein expression of Caspase-8 should be evaluated as a potential biomarker for risk stratification in ALL. The expression of Caspase-8 is frequently downregulated in tumor cells mostly due to epigenetic silencing by promoter hypermethylation. In previous work, we had shown that Methotrexate is able to upregulate the expression of epigenetically downregulated Caspase-8 which is mediated by the transcription factor p53 (Ehrhardt et al, Oncogene 2008). Here we found that Methotrexate (MTX) was able sensitize B- and T-cell leukemia cell lines for apoptosis induction by the Caspase-8 dependent drugs Asparaginase, Cyclophosphamide, Dexamethasone and Doxorubicin. Sensitization by MTX for drug-induced apoptosis was mediated by p53 and Caspase-8 as shown by stable expression of respective small hairpin RNAs introduced by lentiviral transduction. Accoordingly to the data obtained in cell lines, in patient-derived ALL cells with low expression of Caspase-8, MTX sensitized for induction of apoptosis by Asparaginase, Cyclophosphamide, Dexamethasone and Doxorubicin. Transient transfection of siRNA into patient-derived ALL cells revealed that synergistic apoptosis induction by MTX and these drugs was dependent on p53 and Caspase-8. Our results indicate that Caspase-8 is crucial for the high anti-leukemic efficiency of numerous routine cytotoxic drugs and drug combinations. Re-expression of epigenetically downregulated Caspase-8 represents a promising approach to increase efficiency of anti-leukemic therapy. Retrospectively, our data might explain on a molecular level, why clinical empirical studies already revealed a high anti-leukemic efficiency for some of these drug combinations over decades. Routine, decades-known cytotoxic drugs activate signaling mechanisms recognized rather recently such as reversing epigenetic silencing. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Caspase-14—From Biomolecular Basics to Clinical Approach. A Review of Available Data

2021 ◽  
Vol 22 (11) ◽  
pp. 5575
Author(s):  
Agnieszka Markiewicz ◽  
Dawid Sigorski ◽  
Mateusz Markiewicz ◽  
Agnieszka Owczarczyk-Saczonek ◽  
Waldemar Placek
Keyword(s):  
Cell Death ◽  
Physiological Role ◽  
Skin Barrier ◽  
Clinical Aspects ◽  
Clinical Approach ◽  
Search Term ◽  
Caspase Family ◽  
Skin Conditions ◽  
Theoretical Science

Caspase-14 is a unique member of the caspase family—a family of molecules participating in apoptosis. However, it does not affect this process but regulates another form of programmed cell death—cornification, which is characteristic of the epidermis. Therefore, it plays a crucial role in the formation of the skin barrier. The cell death cycle has been a subject of interest for researchers for decades, so a lot of research has been done to expand the understanding of caspase-14, its role in cell homeostasis and processes affecting its expression and activation. Conversely, it is also an interesting target for clinical researchers searching for its role in the physiology of healthy individuals and its pathophysiology in particular diseases. A summary was done in 2008 by Denecker et al., concentrating mostly on the biotechnological aspects of the molecule and its physiological role. However, a lot of new data have been reported, and some more practical and clinical research has been conducted since then. The majority of studies tackled the issue of clinical data presenting the role of caspase in the etiopathology of many diseases such as retinal dysfunctions, multiple malignancies, and skin conditions. This review summarizes the available knowledge on the molecular and, more interestingly, the clinical aspects of caspase-14. It also presents how theoretical science may pave the way for medical research. Methods: The authors analyzed publications available on PubMed until 21 March 2021, using the search term “caspase 14”.

scholarly journals Inhibition of Autophagy Enhances the Antitumor Effect of Thioridazine in Acute Lymphoblastic Leukemia Cells

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 365
Author(s):  
Carina Colturato-Kido ◽  
Rayssa M. Lopes ◽  
Hyllana C. D. Medeiros ◽  
Claudia A. Costa ◽  
Laura F. L. Prado-Souza ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Problem ◽  
Jurkat Cells ◽  
Leukemia Cells ◽  
Peripheral Mononuclear Blood ◽  
Induced Apoptosis ◽  
Cure Rates

Acute lymphoblastic leukemia (ALL) is an aggressive malignant disorder of lymphoid progenitor cells that affects children and adults. Despite the high cure rates, drug resistance still remains a significant clinical problem, which stimulates the development of new therapeutic strategies and drugs to improve the disease outcome. Antipsychotic phenothiazines have emerged as potential candidates to be repositioned as antitumor drugs. It was previously shown that the anti-histaminic phenothiazine derivative promethazine induced autophagy-associated cell death in chronic myeloid leukemia cells, although autophagy can act as a “double-edged sword” contributing to cell survival or cell death. Here we evaluated the role of autophagy in thioridazine (TR)-induced cell death in the human ALL model. TR induced apoptosis in ALL Jurkat cells and it was not cytotoxic to normal peripheral mononuclear blood cells. TR promoted the activation of caspase-8 and -3, which was associated with increased NOXA/MCL-1 ratio and autophagy triggering. AMPK/PI3K/AKT/mTOR and MAPK/ERK pathways are involved in TR-induced cell death. The inhibition of the autophagic process enhanced the cytotoxicity of TR in Jurkat cells, highlighting autophagy as a targetable process for drug development purposes in ALL.

scholarly journals Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis

2007 ◽  
Vol 179 (2) ◽  
pp. 255-267 ◽  
Author(s):  
Karthik Jeganathan ◽  
Liviu Malureanu ◽  
Darren J. Baker ◽  
Susan C. Abraham ◽  
Jan M. van Deursen
Keyword(s):  
Cell Death ◽  
Chromosome Segregation ◽  
Physiological Role ◽  
Mitotic Checkpoint ◽  
Critical Threshold ◽  
Wild Type ◽  
Checkpoint Protein ◽  
Chromosome Missegregation ◽  
Mitotic Checkpoint Protein

The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weakened mitotic checkpoint activity and high percentages of aneuploid cells. Bub1 haploinsufficient mice, which have a milder reduction in Bub1 protein than Bub1 hypomorphic mice, also exhibit reduced checkpoint activity and increased aneuploidy, but to a lesser extent. Although cells from Bub1 hypomorphic and haploinsufficient mice have similar rates of chromosome missegregation, cell death after an aberrant separation decreases dramatically with declining Bub1 levels. Importantly, Bub1 hypomorphic mice are highly susceptible to spontaneous tumors, whereas Bub1 haploinsufficient mice are not. These findings demonstrate that loss of Bub1 below a critical threshold drives spontaneous tumorigenesis and suggest that in addition to ensuring proper chromosome segregation, Bub1 is important for mediating cell death when chromosomes missegregate.

scholarly journals Role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by aziridinylbenzoquinones RH1 and MeDZQ.

2005 ◽  
Vol 52 (4) ◽  
pp. 937-942 ◽  
Author(s):  
Ausra Nemeikaite-Ceniene ◽  
Aldona Dringeliene ◽  
Jonas Sarlauskas ◽  
Narimantas Cenas
Keyword(s):  
Regression Analysis ◽  
Redox Cycling ◽  
Apoptosis Induction ◽  
Electron Reduction ◽  
Induced Apoptosis ◽  
Phenylene Diamine

We aimed to characterize the role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by antitumour quinones RH1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) and MeDZQ (2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone). Digitonin-permeabilized FLK cells catalyzed NADPH-dependent single- and two-electron reduction of RH1 and MeDZQ. At equitoxic concentrations, RH1 and MeDZQ induced apoptosis more efficiently than the nonalkylating duroquinone or H(2)O(2). The antioxidant N,N'-diphenyl-p-phenylene diamine, desferrioxamine, and the inhibitor of NQO1 dicumarol, protected against apoptosis induction by all compounds investigated, but to a different extent. The results of multiparameter regression analysis indicate that RH1 and MeDZQ most likely induce apoptosis via NQO1-linked formation of alkylating species but not via NQO1-linked redox cycling.

scholarly journals Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice

2011 ◽  
Vol 22 (10) ◽  
pp. 1766-1779 ◽  
Author(s):  
Karina Kaczmarek ◽  
Maja Studencka ◽  
Andreas Meinhardt ◽  
Krzysztof Wieczerzak ◽  
Sven Thoms ◽  
...  
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
Specific Gene ◽  
Male Mice ◽  
Terminal Part ◽  
Male Germ Cells ◽  
Germ Cell Apoptosis ◽  
Induced Apoptosis

 Peroxisomal testis-specific 1 gene (Pxt1) is the only male germ cell–specific gene that encodes a peroxisomal protein known to date. To elucidate the role of Pxt1 in spermatogenesis, we generated transgenic mice expressing a c-MYC-PXT1 fusion protein under the control of the PGK2 promoter. Overexpression of Pxt1 resulted in induction of male germ cells’ apoptosis mainly in primary spermatocytes, finally leading to male infertility. This prompted us to analyze the proapoptotic character of mouse PXT1, which harbors a BH3-like domain in the N-terminal part. In different cell lines, the overexpression of PXT1 also resulted in a dramatic increase of apoptosis, whereas the deletion of the BH3-like domain significantly reduced cell death events, thereby confirming that the domain is functional and essential for the proapoptotic activity of PXT1. Moreover, we demonstrated that PXT1 interacts with apoptosis regulator BAT3, which, if overexpressed, can protect cells from the PXT1-induced apoptosis. The PXT1-BAT3 association leads to PXT1 relocation from the cytoplasm to the nucleus. In summary, we demonstrated that PXT1 induces apoptosis via the BH3-like domain and that this process is inhibited by BAT3.

scholarly journals TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects

2017 ◽  
Vol 1 (24) ◽  
pp. 2124-2137 ◽  
Author(s):  
Hirofumi Tenshin ◽  
Jumpei Teramachi ◽  
Asuka Oda ◽  
Ryota Amachi ◽  
Masahiro Hiasa ◽  
...  
Keyword(s):  
Cell Death ◽  
Myeloma Cell ◽  
Apoptosis Induction ◽  
Key Points ◽  
Receptor Activator ◽  
Induced Apoptosis ◽  
Osteoclast Apoptosis

Key Points TRAIL enhances receptor activator of NF-κB ligand–induced osteoclastogenesis and c-FLIP upregulation without osteoclast apoptosis induction. TAK1 inhibition triggers TRAIL-induced apoptosis in osteoclasts, while potentiating TRAIL-induced myeloma cell death.

scholarly journals RIG-I Plays a Dominant Role in the Induction of Transcriptional Changes in Zika Virus-Infected Cells, which Protect from Virus-Induced Cell Death

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1476 ◽  
Author(s):  
Mirjam Schilling ◽  
Anne Bridgeman ◽  
Nicki Gray ◽  
Jonny Hertzog ◽  
Philip Hublitz ◽  
...  
Keyword(s):  
Cell Death ◽  
Zika Virus ◽  
Dominant Role ◽  
A549 Cells ◽  
Effective Control ◽  
Type I ◽  
Type I Ifn ◽  
Structural Protein ◽  
Induced Apoptosis ◽  
The Individual

The Zika virus (ZIKV) has received much attention due to an alarming increase in cases of neurological disorders including congenital Zika syndrome associated with infection. To date, there is no effective treatment available. An immediate response by the innate immune system is crucial for effective control of the virus. Using CRISPR/Cas9-mediated knockouts in A549 cells, we investigated the individual contributions of the RIG-I-like receptors MDA5 and RIG-I to ZIKV sensing and control of this virus by using a Brazilian ZIKV strain. We show that RIG-I is the main sensor for ZIKV in A549 cells. Surprisingly, we observed that loss of RIG-I and consecutive type I interferon (IFN) production led to virus-induced apoptosis. ZIKV non-structural protein NS5 was reported to interfere with type I IFN receptor signaling. Additionally, we show that ZIKV NS5 inhibits type I IFN induction. Overall, our study highlights the importance of RIG-I-dependent ZIKV sensing for the prevention of virus-induced cell death and shows that NS5 inhibits the production of type I IFN.

scholarly journals Side-by-side comparison of BH3-mimetics identifies MCL-1 as a key therapeutic target in AML

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Larissa Ewald ◽  
Jessica Dittmann ◽  
Meike Vogler ◽  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Treatment Options ◽  
B Cell Lymphoma ◽  
Bh3 Mimetics ◽  
Domain 3 ◽  
Functional Relevance ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Agents

AbstractDespite advances in the treatment of acute myeloid leukemia (AML), prognosis of AML patients is still dismal and better treatment options are required. B-cell Lymphoma 2 (BCL-2) homology domain 3 (BH3)-mimetics are emerging as a novel class of apoptosis-inducing agents that are currently being tested for the treatment of different hematological malignancies including AML. Particularly, the selective BCL-2 inhibitor ABT-199/Venetoclax is demonstrating clinical responses and has recently been approved in combination for the treatment of AML. Compounds targeting the related protein MCL-1 have recently entered clinical trials, highlighting the urgency to compare the different BH3-mimetics and identify the most promising antiapoptotic target in AML. We performed a side-by-side comparison of different highly selective and potent BH3-mimetics targeting BCL-2 (ABT-199), MCL-1 (S63845) or BCL-xL (A1331852) in a panel of AML cell lines and primary patient cells. Gene knockdown using siRNAs was utilized to investigate the functional relevance of BCL-2 proteins. Western blotting and immunoprecipitations were used to explore the influence of BH3-mimetics on interactions between pro- and antiapoptotic BCL-2 proteins. A1331852 induced apoptosis only in selected cases, indicating that BCL-xL is not a very promising therapeutic target in AML. However, S63845 displayed higher potency than ABT-199, with more cell lines and primary cells responding to S63845 than to ABT-199. MCL-1 dependency in AML cells was confirmed by siRNA-mediated knockdown of MCL-1, which was sufficient to induce apoptosis. S63845-induced cell death was accompanied by a displacement of the BH3-only protein BIM as well as BAK, resulting in BAK-dependent apoptosis. In contrast, ABT-199-induced cell death was mediated by BAX rather than BAK, indicating distinct non-redundant molecular functions of BCL-2 and MCL-1 in AML. Our study reveals that MCL-1 may be a more prevalent therapeutic target than BCL-2 in AML and identifies BIM and BAK as important mediators of S63845-induced apoptosis in AML.

scholarly journals Expression of a Mitochondrial Peroxiredoxin Prevents Programmed Cell Death in Leishmania donovani

2006 ◽  
Vol 5 (5) ◽  
pp. 861-870 ◽  
Author(s):  
Simone Harder ◽  
Meike Bente ◽  
Kerstin Isermann ◽  
Iris Bruchhaus
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Mitochondrial Membrane ◽  
Leishmania Donovani ◽  
Physiological Role ◽  
Logarithmic Phase ◽  
Insect Vector ◽  
Oxygen Species ◽  
Late Logarithmic Phase

ABSTRACT Leishmania promastigote cells transmitted by the insect vector get phagocytosed by macrophages and convert into the amastigote form. During development and transformation, the parasites are exposed to various concentrations of reactive oxygen species, which can induce programmed cell death (PCD). We show that a mitochondrial peroxiredoxin (LdmPrx) protects Leishmania donovani from PCD. Whereas this peroxiredoxin is restricted to the kinetoplast area in promastigotes, it covers the entire mitochondrion in amastigotes, accompanied by dramatically increased expression. A similar change in the expression pattern was observed during the growth of Leishmania from the early to the late logarithmic phase. Recombinant LdmPrx shows typical peroxiredoxin-like enzyme activity. It is able to detoxify organic and inorganic peroxides and prevents DNA from hydroxyl radical-induced damage. Most notably, Leishmania parasites overexpressing this peroxiredoxin are protected from hydrogen peroxide-induced PCD. This protection is also seen in promastigotes grown to the late logarithmic phase, also characterized by high expression of this peroxiredoxin. Apparently, the physiological role of this peroxiredoxin is stabilization of the mitochondrial membrane potential and, as a consequence, inhibition of PCD through removal of peroxides.

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