Mitochondria-assisted cell suicide: a license to kill

Regula, Kelly M.

doi:10.1016/s0022-2828(03)00118-4

Cited by 75 publications

(38 citation statements)

References 83 publications

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“…Dcm correlates with mitochondrial outer-membrane permeability during PCD [59]. The maintenance of Dcm and inhibition of cytochrome c release in LdDNA-transfected macrophages, demonstrated in the present study, reflect the maintenance of mitochondrial integrity by L. donovani.…”

Section: Discussionsupporting

confidence: 64%

Unmethylated CpG motifs in the L. donovani DNA regulate TLR9-dependent delay of programmed cell death in macrophages

Das

Ghosh

Singh

et al. 2014

Journal of Leukocyte Biology

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Regulation of macrophage PCD plays an important role in pathogenesis of leishmaniasis. However, the precise involvement of any parasite molecule in this process remains uncertain. In the current study, in silico wide analysis demonstrated that genes in the Leishmania donovani genome are highly enriched for CpG motifs, with sequence frequency of 8.7%. Here, we show that unmethylated species-specific CpG motifs in LdDNA significantly (P = 0.01) delay macrophage PCD by endosomal interaction with TLR9 via the adaptor protein MyD88. Importantly, LdDNA triggered high levels of luciferase activity (P = 0.001) under NF-kB-dependent transcription in HEK-TLR9 cells. Furthermore, the activation of caspases in macrophages was inhibited (P = 0.001) in the presence of LdDNA. Notably, the delay of PCD was mediated by modulation of the antiapoptotic proteins, Mcl-1 and Bfl-1, and impairment of loss of Dcm in macrophages through the neutralization of oxidative and nitrosative stress. The inhibition of caspase activation and up-regulation of Mcl-1 by LdDNA were TLR9 dependent. Analysis of the targets of LdDNA identified an early activation of the TLR9-dependent PI3K/Akt and SFK pathways, which were required for the observation of the antiapoptotic effects in macrophages. Moreover, we demonstrate that LdDNA modulates the TLR9-IkB-a pathway by promoting the tyrosine phosphorylation of TLR9 and the TLR9-mediated recruitment of Syk kinase. The results have identified a novel, TLR9-dependent antiapo ptotic function of LdDNA, which will provide new opportunities for discovering and evaluating molecular targets for drug and vaccine designing against VL.

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Section: Discussionsupporting

confidence: 64%

Unmethylated CpG motifs in the L. donovani DNA regulate TLR9-dependent delay of programmed cell death in macrophages

Das

Ghosh

Singh

et al. 2014

Journal of Leukocyte Biology

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“…Thus the question arises as to what molecular mechanisms upstream of caspase-3 activation could be regulated by the HO system. Higher levels of Apaf-1 in rats lacking HO-1 may suggest a link between HO-1 and the intrinsic mitochondrial pathway of apoptosis (37,53). The intrinsic pathway of apoptosis involves permeabilization of the outer membrane of mitochondria with release of proapoptotic proteins, such as cytochrome c (12,24).…”

Section: Discussionmentioning

confidence: 99%

Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway

Olszanecki¹,

Rezzani²,

Omura³

et al. 2007

American Journal of Physiology-Renal Physiology

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NG. Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway. Am J Physiol Renal Physiol 292: F148 --F157, 2007. First published August 29, 2006; doi:10.1152/ajprenal.00261.2006.-Apoptosis has been shown to contribute to the development of acute and chronic renal failure. The antiapoptotic action of the heme oxygenase (HO) system may represent an important protective mechanism in kidney pathology. We examined whether the lack of HO-1 would influence apoptosis in clipped kidneys of two-kidney, one-clip (2K1C) rats. Five-day-old Sprague-Dawley rats were injected in the left ventricle with Ϸ5 ϫ 10 9 colony-forming units/ml of retrovirus containing rat HO-1 antisense (LSN-RHO-1-AS) or control retrovirus (LXSN). After 3 mo, a 0.25-mm U-shaped silver clip was placed around the left renal artery. Animals were killed 3 wk later. Clipping the renal artery in LSN-RHO-1-AS rats did not result in increased HO-1 expression. In contrast to LXSN animals, 2K1C LSN-RHO-1-AS rats showed increased expression of cyclooxygenase 2 (COX-2) and higher 3-nitrotyrosine (3-NT) content as well as increased expression of the proapoptotic protein Apaf-1 and caspase-3 activity. Clipping the renal artery in LXSN rats resulted in increased expression of the antiapoptotic proteins Bcl-2 and Bcl-xl, while clipping the renal artery in LSN-RHO-1-AS rats did not change Bcl-2 levels and decreased the levels of Bcl-xl. Treatment of LSN-RHO-1-AS rats with cobalt protoporphyrin resulted in induction of renal HO-1, which was accompanied by decreases in blood pressure, COX-2, 3-NT, and caspase-3 activity, and increased expression of anti-apoptotic molecules (Bcl-2, Bcl-xl, Akt and p-Akt) in the clipped kidneys. These findings underscore the prominent role of HO-1 in counteracting apoptosis in this 2K1C renovascular hypertension model. heme oxygenase; hypertension; 2K1C; apoptosis; oxidative stress HEME OXYGENASE (HO) CATALYZES the rate-liming step in heme degradation, producing iron, carbon monoxide (CO), and biliverdin, which is rapidly converted to bilirubin. Two major HO isoforms, the products of two distinct genes, have been described: HO-1, an inducible isoform, and HO-2, a constitutively expressed isoform. HO-1 is induced by heme and a variety of nonheme stimuli, including heavy metals, reactive oxygen species (ROS), nitric oxide (NO), ANG II, endotoxin, and cytokines (1, 2). In general, upregulation of HO-1 serves as an adaptive and beneficial response to these stimuli.Induction of HO-1 has been shown to play a cytoprotective role in renal injury secondary to rhabdomyolysis (32), ischemia-reperfusion injury (31), glomerulonephritis (16), renal transplant rejection (7), and nephrotoxins (e.g., cisplatin) (4). Under these conditions, the protective effects of HO were related to degradation of the toxic free-heme moiety and stimulation of efflux of prooxidant iron from the cells, and also to the biological actions of bilirubin, a potent antioxidant (41) and CO, a vasodilatory and anti-infla...

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“…Oxygen deprivation provokes mitochondrial permeability transition pore (PTP) opening, loss of mitochondrial membrane potential (⌬⌿m), cytochrome c release, and cell death of ventricular myocytes. 2,3 Previously, we have established the mitochondrial death protein Bnip3 as an integral component of the intrinsic death pathway during hypoxic injury of postnatal ventricular myocytes. 4,5 However, the signaling pathways and transcriptional processes that regulate Bnip3 transcription remain poorly defined.…”

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confidence: 99%

The Cell Cycle Factor E2F-1 Activates Bnip3 and the Intrinsic Death Pathway in Ventricular Myocytes

Yurkova

Shaw

Blackie

et al. 2008

Circulation Research

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Abstract-The cell cycle factor E2F-1 is known to regulate a variety of cellular processes including apoptosis. Previously we showed that disruption of Rb-E2F-1 complexes provoked apoptosis of postmitotic adult and neonatal ventricular myocytes; however, the underlying mechanism was undetermined. In this report, we show that E2F-1 provokes cell death of ventricular myocytes through a mechanism that directly impinges on the intrinsic death pathway. Furthermore, we show mechanistically that the hypoxia-inducible death factor Bnip3 is a direct transcriptional target of E2F-1 that is necessary and sufficient for E2F-1-induced cell death. Expression of E2F-1 resulted in a 4.9-fold increase (PϽ0.001) in nucleosomal DNA fragmentation and cell death by Hoechst 33258 dye and vital staining. E2F-1 provoked mitochondrial perturbations that were consistent with permeability transition pore opening. As determined by quantitative real-time PCR analysis, a 6.2-fold increase (PϽ0.001) in endogenous Bnip3 gene transcription was observed in cells expressing wild-type E2F-1 but not in cells expressing a mutation of E2F-1 defective for DNA binding. Rb, the principle regulator of cellular E2F-1 activity, was proteolytically cleaved and inactivated in ventricular myocytes during hypoxia. Consistent with the proteolytic cleavage of Rb, chromatin immunoprecipitation analysis revealed increased binding of E2F-1 to the Bnip3 promoter during hypoxia, a finding concordant with the induction of Bnip3 gene transcription. The Bnip3 homolog Nix/Bnip3L was unaffected in ventricular myocytes by either E2F-1 or hypoxia. 4,5 However, the signaling pathways and transcriptional processes that regulate Bnip3 transcription remain poorly defined.The cellular factor E2F-1 is the archetypal member of a family of transcription factors first characterized for their ability to activate genes required for G 1 exit and DNA synthesis. 6 To date, at least 6 homologs of E2F (E2F-1 to E2F-6), together with their dimerization partners DRFT1-polypeptides 1 and 2 (DP-1 and DP-2), have been identified. 7,8 Notably, E2F-1 is uniquely distinguished from other E2F proteins by its propensity to provoke apoptosis, 7-9 yet the underlying mechanism for this property of E2F-1 is, at best, poorly understood. In cells, E2F-1 interacts with the retinoblastoma gene product Rb via its L-X-C-X-E motif, which is crucial for suppressing cellular E2F activity and E2F-1-dependent promoters. 10 Accordingly, loss-of-function mutations or germ line deletion of Rb in mice results in increased E2F-1 activity and apoptosis. 11 Furthermore, the unexpected and counterintuitive tumorigenesis in E2F-1 Ϫ/Ϫ mice underscores the importance of E2F-1 as a key regulator of apoptosis. 12 Previously, we have shown that displacement of E2F-1 from Rb by viral oncoproteins or overexpression of E2F-1 alone was sufficient to provoke apoptosis of ventricular Original received September 21, 2007; revision received November 7, 2007; accepted December 12, 2007. myocytes; however, the underlying mechanism(s) was...

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Mitochondria-assisted cell suicide: a license to kill

Cited by 75 publications

References 83 publications

Unmethylated CpG motifs in the L. donovani DNA regulate TLR9-dependent delay of programmed cell death in macrophages

Unmethylated CpG motifs in the L. donovani DNA regulate TLR9-dependent delay of programmed cell death in macrophages

Genetic suppression of HO-1 exacerbates renal damage: reversed by an increase in the antiapoptotic signaling pathway

The Cell Cycle Factor E2F-1 Activates Bnip3 and the Intrinsic Death Pathway in Ventricular Myocytes

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