Novobiocin induces apoptosis-like cell death in topoisomerase II over-expressing arsenite resistant Leishmania donovani

Singh, Gaganmeet; Jayanarayan, K. G.; Dey, Chinmoy Sankar

doi:10.1016/j.molbiopara.2005.01.014

Cited by 47 publications

(37 citation statements)

References 51 publications

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“…Still, intriguingly, some reports have described 'caspase-like' activities in these protozoa. 16,[29][30][31][32][33] The issue, therefore, is yet unanswered. Even if apoptosis-like in these divergent organisms appears mainly caspase-independent, it remains probable that other proteases are involved, but they would be either simply different or too distant to be identified from sequence data.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

et al. 2008

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The link between nucleocytoplasmic transport and apoptosis remains controversial. Nucleocytoplasmic exchange of molecules seems indeed essential for the initiation and execution of the apoptotic programme; but inhibition of nuclear transport factors may also represent a powerful apoptotic trigger. The GTPase Ran (together with its partners), first discovered to be essential in nucleocytoplasmic transport, has multiple key functions in cell biology, and particularly in spindle assembly, kinetochore function and nuclear envelope assembly. Among the Ran partners studied, NTF2 appears to be solely involved in nucleocytoplasmic transport. Here, we localised Ran and several of its partners, RanBP1, CAS and NTF2, at the nuclear membrane in the trypanosomatid Leishmania major. Remarkably, these proteins fused to GFP decorated a perinuclear 'collar' of about 15 dots, colocalising at nuclear pore complexes with the homologue of nucleoporin Sec13. In the other trypanosomatid Trypanosoma brucei, RNAi knockdown of the expression of the corresponding genes resulted in an apoptosis-like phenomenon. These phenotypes show that Ran and its partners have a key function in trypanosomatids like they have in mammals. Our data, notably those about TbNTF2 RNAi, support the idea that active nucleocytoplasmic transport is not essential for the initiation and execution of apoptosis, and, rather, the impairment of this transport constitutes an intrinsic signal for triggering PCD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

et al. 2008

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“…Externalization of phosphatidylserine on the outer membrane of parasites with and without treatment was determined by using Annexin V labeling kit following the manufacturer's protocol (Annexin-V-FITC Apoptosis Detection Kit Alexis, Lausen, Switzerland) (Singh et al, 2005). Briefly, parasites (2 Â 10 6 ) were washed with PBS and centrifuged at 500g for 5 min.…”

Section: Determination Of Apoptosis By Annexin Vmentioning

confidence: 99%

TTAS a new stilbene derivative that induces apoptosis in Leishmania infantum

Tolomeo

Roberti

Scapozza

et al. 2013

Experimental Parasitology

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“…A number of specific synthetic substrates and inhibitors have been developed and used to determine the enzymatic properties of most mammalian caspases. Such synthetic substrates and inhibitors were also used to identify caspase-like activities in many organisms, including yeasts (26,27,38), plants (3,18,23), and protozoa (1,6,19,22,24,(34)(35)(36). However, it was shown recently that metacaspases of Arabidopsis thaliana expressed in Escherichia coli were unable to cleave caspase-specific substrates but cleaved substrates containing an arginine or lysine residues at the P1 position (40,41).…”

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confidence: 99%

“…Many features of metazoan apoptosis have been observed in both developmen-tal stages of Leishmania undergoing PCD (reviewed in references 2, 10, and 30). It was also shown that caspase-like activities were associated with parasite PCD (6,24,(34)(35)(36). We have reported previously that a DEVDase activity was activated in live L. donovani parasites either in late stationary cells or in parasites treated with the antileishmanial drug amphotericin B (24).…”

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Characterization of Metacaspases with Trypsin-Like Activity and Their Putative Role in Programmed Cell Death in the Protozoan Parasite Leishmania

et al. 2007

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In this report, we have characterized two metacaspases of Leishmania donovani, L. donovani metacaspase-1 (LdMC1) and LdMC2. These two proteins show 98% homology with each other, and both contain a characteristic C-terminal proline-rich domain. Both genes are transcribed in promastigotes and axenic amastigotes of L. donovani; however, LdMC1 shows increased mRNA levels in axenic amastigotes. An anti-LdMC antibody was obtained and showed reactivity with a single ϳ42-kDa protein band in both promastigote and axenic amastigote parasite whole-cell lysates by Western blotting. Pulse-chase experiments suggest that LdMCs are not synthesized as proenzymes, and immunofluorescence studies show that LdMCs are associated with the acidocalcisome compartments of L. donovani. Enzymatic assays of immunoprecipitated LdMCs show that native LdMCs efficiently cleave trypsin substrates and are unable to cleave caspase-specific substrates. Consistently, LdMC activity is insensitive to caspase inhibitors and is efficiently inhibited by trypsin inhibitors, such as leupeptin, antipain, and N ␣ -tosyl-L-lysine-chloromethyl ketone (TLCK). In addition, our results show that LdMC activity was induced in parasites treated with hydrogen peroxide, a known trigger of programmed cell death (PCD) in Leishmania and that parasites overexpressing metacaspases are more sensitive to hydrogen peroxide-induced PCD. These findings suggest that Leishmania metacaspases are not responsible for the caspase-like activities reported in this organism and suggest a possible role for LdMCs as effector molecules in Leishmania PCD.Metacaspases constitute a new family of caspase-related proteins recently described by Uren et al. (39). They have been identified by bioinformatic analysis and are found in plants, fungi, and parasitic protozoa but are absent in mammals (39). Metacaspases belong to the CD clan of cysteine peptidases with six other families, including caspases and paracaspases (29). Metacaspases are structurally related to caspases and show conservation of cysteine and histidine amino acid residues involved in the Cys-His catalytic dyad of the active domains of caspase (39). Caspases have been shown to play a central role in programmed cell death of mammalian cells, also called apoptosis (reviewed in reference 14). To date, no caspase gene has been identified in plants, yeasts, or protozoan parasites. However, since these organisms possess one or more metacaspases, it is conceivable that like caspases in mammalian cells, these caspase-related proteases could be involved in the PCD pathways in these organisms. In that regard, the Saccharomyces cerevisiae metacaspase YCA1 and the Norway spruce metacaspase mcII-Pa have been shown recently to be directly implicated in PCD in these organisms (4, 28). To date, however, the possible role of metacaspases in PCD of protozoan parasites remains to be demonstrated.Little is known about the enzymatic properties of metacaspases. In contrast, the related caspase enzymes are wellcharacterized cysteine-dependent aspartate-s...

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Novobiocin induces apoptosis-like cell death in topoisomerase II over-expressing arsenite resistant Leishmania donovani

Cited by 47 publications

References 51 publications

Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

Inhibition of active nuclear transport is an intrinsic trigger of programmed cell death in trypanosomatids

TTAS a new stilbene derivative that induces apoptosis in Leishmania infantum

Characterization of Metacaspases with Trypsin-Like Activity and Their Putative Role in Programmed Cell Death in the Protozoan Parasite Leishmania

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