scholarly journals AEBP1 down regulation induced cell death pathway depends on PTEN status of glioma cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Swati Sinha ◽  
Arun Renganathan ◽  
Prathima B. Nagendra ◽  
Vasudeva Bhat ◽  
Brian Steve Mathew ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cellular Proliferation ◽  
Ectopic Expression ◽  
Glioma Cells ◽  
Down Regulation ◽  
Over Expression ◽  
Cell Death Pathway ◽  
Dependent Cell ◽  
Parp 1

Abstract Glioblastoma (GBM) is the most common aggressive form of brain cancer with overall dismal prognosis (10–12 months) despite all current multimodal treatments. Previously we identified adipocyte enhancer binding protein 1 (AEBP1) as a differentially regulated gene in GBM. On probing the role of AEBP1 over expression in glioblastoma, we found that both cellular proliferation and survival were affected upon AEBP1 silencing in glioma cells, resulting in cell death. In the present study we report that the classical caspase pathway components are not activated in cell death induced by AEBP1 down regulation in PTEN-deficient (U87MG and U138MG) cells. PARP-1 was not cleaved but over-activated under AEBP1 down regulation which leads to the synthesis of PAR in the nucleus triggering the release of AIF from the mitochondria. Subsequently, AIF translocates to the nucleus along with MIF causing chromatinolysis. AEBP1 positively regulates PI3KinaseCβ by the binding to AE-1 binding element in the PI3KinaseCβ promoter. Loss of PI3KinaseCβ expression under AEBP1 depleted condition leads to excessive DNA damage and activation of PARP-1. Furthermore, over expression of PIK3CB (in trans) in U138MG cells prevents DNA damage in these AEBP1 depleted cells. On the contrary, AEBP1 down regulation induces caspase-dependent cell death in PTEN-proficient (LN18 and LN229) cells. Ectopic expression of wild-type PTEN in PTEN-deficient U138MG cells results in the activation of canonical caspase and Akt dependent cell death. Collectively, our findings define AEBP1 as a potential oncogenic driver in glioma, with potential implications for therapeutic intervention.

scholarly journals DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lama Tarayrah-Ibraheim ◽  
Elital Chass Maurice ◽  
Guy Hadary ◽  
Sharon Ben-Hur ◽  
Alina Kolpakova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Germ Cells ◽  
Nuclear Translocation ◽  
Primordial Germ Cells ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Dnase Ii ◽  
Cell Death Pathway ◽  
Parp 1

AbstractDuring Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.

Follicular expression of a human β-cell leukaemia/lymphoma-2 (Bcl-2) transgene does not decrease atresia or increase ovulation rate in swine

2005 ◽  
Vol 17 (4) ◽  
pp. 457 ◽  
Author(s):  
H. D. Guthrie ◽  
R. J. Wall ◽  
V. G. Pursel ◽  
J. A. Foster-Frey ◽  
D. M. Donovan ◽  
...  
Keyword(s):  
Cell Death ◽  
Ectopic Expression ◽  
Immunohistochemical Analysis ◽  
Polymerase Chain Reaction Analysis ◽  
Ovulation Rate ◽  
Cell Leukaemia ◽  
Α Subunit ◽  
Cell Death Pathways ◽  
Cell Death Pathway ◽  
Dependent Cell

Transgenic (TG) gilts carrying a human Bcl-2 cDNA transgene driven by mouse inhibin-α subunit promoter were produced and evaluated to determine if ectopic expression of Bcl-2 in the ovaries would decrease the frequency of atresia in antral follicles and increase ovulation rate. Immunohistochemical analysis showed that the Bcl-2 transgene protein was expressed in granulosa and theca cells, in 86% of healthy and 54% of atretic follicles analysed in TG prepubertal and Day 50 pregnant gilts combined (n = 24). In contrast, Bcl-2 transgene protein was expressed in only 1.4% of healthy and 0% of atretic follicles in non-TG littermates (n = 13). Real-time reverse transcription–polymerase chain reaction analysis confirmed that human Bcl-2 was expressed in follicles of TG gilts. The atresia rate for the TG and non-TG groups did not differ (P > 0.05) for prepubertal (45 v. 59%) and Day 50 pregnant gilts (53 v. 52%) respectively. The mean ± s.e.m. ovulation rate did not differ (P > 0.5) between TG (15.9 ± 0.8, n = 12) and non-TG (16.4 ± 0.6, n = 7) Day 50 pregnant gilts. The molecular basis of the failure of ectopic Bcl-2 expression to increase the ratio of healthy to atretic follicles is unknown, but it is possible that the activity of the mitochondrial-dependent cell death pathway was not neutralized by ectopic expression of human Bcl-2 or that other cell death pathways compensated for the decreased mitochondrial-dependent cell death.

scholarly journals Control of a programmed cell death pathway in Pseudomonas aeruginosa by an antiterminator

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer M. Peña ◽  
Samantha M. Prezioso ◽  
Kirsty A. McFarland ◽  
Tracy K. Kambara ◽  
Kathryn M. Ramsey ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Dna Damage ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Rna Polymerase ◽  
Virulence Genes ◽  
Opportunistic Pathogen ◽  
Transcription Activator ◽  
Present Evidence ◽  
Cell Death Pathway

AbstractIn Pseudomonas aeruginosa the alp system encodes a programmed cell death pathway that is switched on in a subset of cells in response to DNA damage and is linked to the virulence of the organism. Here we show that the central regulator of this pathway, AlpA, exerts its effects by acting as an antiterminator rather than a transcription activator. In particular, we present evidence that AlpA positively regulates the alpBCDE cell lysis genes, as well as genes in a second newly identified target locus, by recognizing specific DNA sites within the promoter, then binding RNA polymerase directly and allowing it to bypass intrinsic terminators positioned downstream. AlpA thus functions in a mechanistically unusual manner to control the expression of virulence genes in this opportunistic pathogen.

scholarly journals The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Genes ◽  
2019 ◽  
Vol 10 (6) ◽  
pp. 453 ◽  
Author(s):  
Arianna Tolone ◽  
Soumaya Belhadj ◽  
Andreas Rentsch ◽  
Frank Schwede ◽  
François Paquet-Durand
Keyword(s):  
Cell Death ◽  
Gene Mutations ◽  
Interdisciplinary Cooperation ◽  
Response To Treatment ◽  
Common Denominator ◽  
Photoreceptor Degeneration ◽  
Diverse Range ◽  
Cell Death Pathway ◽  
Cgmp Signaling ◽  
Dependent Cell

Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.

Poly(ADP-ribose) polymerase-1 gene ablation protects mice from ischemic renal injury

2005 ◽  
Vol 288 (2) ◽  
pp. F387-F398 ◽  
Author(s):  
Jianfeng Zheng ◽  
Kishor Devalaraja-Narashimha ◽  
Kurinji Singaravelu ◽  
Babu J. Padanilam
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Mouse Model ◽  
Renal Injury ◽  
Atp Depletion ◽  
Inflammatory Cascade ◽  
Renal Functions ◽  
Atp Levels ◽  
Ischemic Renal Injury ◽  
Parp 1

Increased generation of reactive oxygen species (ROS) and the subsequent DNA damage and excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1) have been implicated in the pathogenesis of ischemic injury. We previously demonstrated that pharmacological inhibition of PARP protects against ischemic renal injury (IRI) in rats (Martin DR, Lewington AJ, Hammerman MR, and Padanilam BJ. Am J Physiol Regul Integr Comp Physiol 279: R1834–R1840, 2000). To further define the role of PARP-1 in IRI, we tested whether genetic ablation of PARP-1 attenuates tissue injury after renal ischemia. Twenty-four hours after reperfusion following 37 min of bilateral renal pedicle occlusion, the effects of the injury on renal functions in PARP−/− and PARP+/+ mice were assessed by determining glomerular filtration rate (GFR) and the plasma levels of creatinine. The levels of plasma creatinine were decreased and GFR was augmented in PARP−/− mice. Morphological evaluation of the kidney tissues showed that the extent of damage due to the injury in PARP−/− mice was less compared with their wild-type counterparts. The levels of ROS and DNA damage were comparable in the injured kidneys of PARP+/+ and PARP−/− mice. PARP activity was induced in ischemic kidneys of PARP+/+ mice at 6–24 h postinjury. At 6, 12, and 24 h after injury, ATP levels in the PARP+/+ mice kidney declined to 28, 26, and 43%, respectively, whereas it was preserved close to normal levels in PARP−/− mice. The inflammatory cascade was attenuated in PARP−/− mice as evidenced by decreased neutrophil infiltration and attenuated expression of inflammatory molecules such as TNF-α, IL-1β, and intercellular adhesion molecule-1. At 12 h postinjury, no apoptotic cell death was observed in PARP−/− mice kidneys. However, by 24 h postinjury, a comparable number of cells underwent apoptosis in both PARP−/− and PARP+/+ mice kidneys. Thus activation of PARP post-IRI contributes to cell death most likely by ATP depletion and augmentation of the inflammatory cascade in the mouse model. PARP ablation preserved ATP levels, renal functions, and attenuated inflammatory response in the setting of IRI in the mouse model. PARP inhibition may have clinical efficacy in preventing the progression of acute renal failure complications.

scholarly journals Asc Modulates the Function of NLRC4 in Response to Infection of Macrophages by Legionella pneumophila

mBio ◽  
2011 ◽  
Vol 2 (4) ◽  
Author(s):  
Christopher L. Case ◽  
Craig R. Roy
Keyword(s):  
Cell Death ◽  
Legionella Pneumophila ◽  
Fluorescent Protein ◽  
Microbial Infection ◽  
Content Type ◽  
Caspase 1 ◽  
Cell Death Pathway ◽  
Dependent Cell ◽  
Green Fluorescent ◽  
In Cells

ABSTRACTNucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) activate caspase-1 in response to a variety of bacterium-derived signals in macrophages. NLR-mediated activation of caspase-1 byLegionella pneumophilaoccurs through both an NLRC4/NAIP5-dependent pathway and a pathway requiring the adapter protein Asc. Both pathways are needed for maximal activation of caspase-1 and for the release of the cytokines interleukin-1β (IL-1β) and IL-18. Asc is not required for caspase-1-dependent pore formation and cell death induced upon infection of macrophages byL. pneumophila. Here, temporal and spatial localization of caspase-1-dependent processes was examined to better define the roles of Asc and NLRC4 during infection. Imaging studies revealed that caspase-1 localized to a single punctate structure in infected cells containing Asc but not in cells lacking this adapter. Both endogenous Asc and ectopically produced NLRC4 tagged with green fluorescent protein (GFP) were found to localize to caspase-1 puncta followingL. pneumophilainfection, suggesting that NLRC4 and Asc coordinate signaling through this complex during caspase-1 activation. Formation of caspase-1-containing puncta correlated with caspase-1 processing, suggesting a role for the Asc/NLRC4/caspase-1 complex in caspase-1 cleavage. In cells deficient for Asc, NLRC4 did not assemble into discrete puncta, and pyroptosis occurred at an accelerated rate. These data indicate that Asc mediates integration of NLR components into caspase-1 processing platforms and that recruitment of NLR components into an Asc complex can dampen pyroptotic responses. Thus, a negative feedback role of complexes containing Asc may be important for regulating caspase-1-mediated responses during microbial infection.IMPORTANCECaspase-1 is a protease activated during infection that is central to the regulation of several innate immune pathways. Studies examining the macromolecular complexes containing this protein, known as inflammasomes, have provided insight into the regulation of this protease. This work demonstrates that the intracellular bacteriumLegionella pneumophilainduces formation of complexes containing caspase-1 by multiple mechanisms and illustrates that an adapter molecule called Asc integrates signals from multiple independent upstream caspase-1 activators in order to assemble a spatially distinct complex in the macrophage. There were caspase-1-associated activities such as cytokine processing and secretion that were controlled by Asc. Importantly, this work uncovered a new role for Asc in dampening a caspase-1-dependent cell death pathway called pyroptosis. These findings suggest that Asc plays a central role in controlling a distinct subset of caspase-1-dependent activities by both assembling complexes that are important for cytokine processing and suppressing processes that mediate pyroptosis.

scholarly journals Eagle Effect in Nonreplicating Persister Mycobacteria

2015 ◽  
Vol 59 (12) ◽  
pp. 7786-7789 ◽  
Author(s):  
Mu-Lu Wu ◽  
Jasmie Tan ◽  
Thomas Dick
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Dose Response ◽  
Mycobacterium Smegmatis ◽  
Content Type ◽  
Cell Death Pathway ◽  
Low Concentrations ◽  
Eagle Effect ◽  
Dependent Cell ◽  
Gyrase Inhibitors

ABSTRACTWe determined the microbicidal activities of antibacterials against nonreplicatingMycobacterium smegmatisgrown in a starvation-based Loebel model for persistence. Whereas most drugs lost their activity, fluoroquinolones retained lethal potency. Dose-response characterizations showed a paradoxical more-drug-kills-less Eagle effect. Pretreatment of cultures with chloramphenicol blocked the lethal action of the gyrase inhibitors. These results suggest that fluoroquinolones at low concentrations trigger a protein synthesis-dependent cell death pathway and shut off this suicide pathway at elevated concentrations.

scholarly journals Down-Regulation of miR-23a-3p Mediates Irradiation-Induced Neuronal Apoptosis

2020 ◽  
Vol 21 (10) ◽  
pp. 3695 ◽  
Author(s):  
Boris Sabirzhanov ◽  
Oleg Makarevich ◽  
James Barrett ◽  
Isabel L. Jackson ◽  
Alan I. Faden ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cytochrome C ◽  
Neuronal Apoptosis ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Negative Regulator ◽  
Down Regulation ◽  
Bcl2 Family ◽  
Mitochondrial Outer Membrane Permeabilization

Radiation-induced central nervous system toxicity is a significant risk factor for patients receiving cancer radiotherapy. Surprisingly, the mechanisms responsible for the DNA damage-triggered neuronal cell death following irradiation have yet to be deciphered. Using primary cortical neuronal cultures in vitro, we demonstrated that X-ray exposure induces the mitochondrial pathway of intrinsic apoptosis and that miR-23a-3p plays a significant role in the regulation of this process. Primary cortical neurons exposed to irradiation show the activation of DNA-damage response pathways, including the sequential phosphorylation of ATM kinase, histone H2AX, and p53. This is followed by the p53-dependent up-regulation of the pro-apoptotic Bcl2 family molecules, including the BH3-only molecules PUMA, Noxa, and Bim, leading to mitochondrial outer membrane permeabilization (MOMP) and the release of cytochrome c, which activates caspase-dependent apoptosis. miR-23a-3p, a negative regulator of specific pro-apoptotic Bcl-2 family molecules, is rapidly decreased after neuronal irradiation. By increasing the degradation of PUMA and Noxa mRNAs in the RNA-induced silencing complex (RISC), the administration of the miR-23a-3p mimic inhibits the irradiation-induced up-regulation of Noxa and Puma. These changes result in an attenuation of apoptotic processes such as MOMP, the release of cytochrome c and caspases activation, and a reduction in neuronal cell death. The neuroprotective effects of miR-23a-3p administration may not only involve the direct inhibition of pro-apoptotic Bcl-2 molecules downstream of p53 but also include the attenuation of secondary DNA damage upstream of p53. Importantly, we demonstrated that brain irradiation in vivo results in the down-regulation of miR-23a-3p and the elevation of pro-apoptotic Bcl2-family molecules PUMA, Noxa, and Bax, not only broadly in the cortex and hippocampus, except for Bax, which was up-regulated only in the hippocampus but also selectively in isolated neuronal populations from the irradiated brain. Overall, our data suggest that miR-23a-3p down-regulation contributes to irradiation-induced intrinsic pathways of neuronal apoptosis. These regulated pathways of neurodegeneration may be the target of effective neuroprotective strategies using miR-23a-3p mimics to block their development and increase neuronal survival after irradiation.

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