Separase is a marker for prognosis and mitotic activity in breast cancer

Gurvits, Natalia; Löyttyniemi, Eliisa; Nykänen, Marjukka; Kuopio, Teijo; Kronqvist, Pauliina; Talvinen, Kati

doi:10.1038/bjc.2017.301

Cited by 25 publications

(21 citation statements)

References 42 publications

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“…In order to investigate the mechanism of anticryptosporidial activity we evaluated expression proliferation (separine) and apoptosis markers (metacaspase) in the parasite. We observed a down regulation in separine expression (also known as separase) which is implicated chromatin regulation during meiosis and mitosis processes 24 , this finding suggest that EA may be blocking proliferation through NDK inhibition as observed in silencing experiments, however also we observed an up regulation of metacaspase which suggest that other mechanisms may be involved in parasite killing. EA has showed multiple benefits to human health trough enhancement of immune system or epithelial barrier 25-27 , thus we speculate that EA has a dual effect on Cryptosporidium by reducing the infection trough the activation of host pathways (e.g.…”

Section: Discussionsupporting

confidence: 66%

Gene silencing in Cryptosporidium: A rapid approach to identify novel targets for drug development

Castellanos-González

Martinez-Traverso

et al. 2019

Preprint

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24 25 26 27 2 28Abstract: 29 Background: Cryptosporidiosis is a major cause of diarrheal disease. However, the only drug 30 approved for cryptosporidiosis does not work well in high risk populations. Therefore, novel 31 drugs are urgently needed. Then, the identification of novel is necessary to develop new 32 therapies against this parasite. Recently, we have developed a rapid method to block gene 33 expression in Cryptosporidium by using pre-assembled complexes of Cryptosporidium 34 antisense RNA and human protein with slicer activity (Argonaute 2). We hypothesized that 35 structural proteins, proteases, enzymes nucleotide synthesis and transcription factors are 36 essential for parasite development, thus in this work we knock down expression of 4 selected 37 genes: Actin, Apicomplexan DNA-binding protein (AP2), Rhomboid protein 1 (Rom 1) and 38 nucleoside diphosphate kinase (NDK) and elucidated its role during invasion, proliferation and 39 egress of Cryptosporidium. 40 41 Methods: We used protein transfection reagents (PTR) to introduce pre-assembled complexes 42 of antisense RNA and human Argonaute 2 into Cryptosporidium parvum oocysts, the complexes 43 blocked expression of Actin (Act), Transcription factor AP2 (AP2), nucleoside diphosphate 44 kinase (DKN), and rhomboid protein 1 (Rom1). After gene silencing, we evaluated parasite 45 reduction using In vitro models of excystation, invasion, proliferation and egress. We evaluated 46 the potency of ellagic acid, a nucleoside diphosphate kinase inhibitor for anti-cryptosporidial 47 activity using a model of in vitro infection with human HCT-8 cells. 48 49 Results: Silencing of Act, AP2, NDK and Rom1 reduce significantly invasion, proliferation and 50 egress of Cryptosporidium. We showed that silencing of NDK markedly inhibited 51 Cryptosporidium proliferation. This was confirmed by demonstration that ellagic acid reduced 52 the number of parasites at micro molar concentrations (EC 50 =15-30 µM) without showing any 53 toxic effect on human cells. 54 55 Conclusions: Overall the results confirmed the usefulness RNA silencing can be used to 56 identify novel targets for drug development against Cryptosporidium. We identified ellagic acid 57 (EA), a nucleoside diphosphate kinase inhibitor also blocks Cryptosporidium proliferation. Since 58 EA is a dietary supplement approved for human use, then this compound should be studied as 59 a potential treatment for cryptosporidiosis. 3 60 Author summary 61 The World Health Organization reports diarrhea kills around 760,000 children under five every 62 year. Cryptosporidium infection is a leading cause of diarrhea morbidity and mortality. Current 63 therapies to treat this infection are suboptimal, therefore novel treatments are urgently needed. 64 We used genetic tools to identify novel targets for drug development, thus in this work we 65 evaluated the role of 4 genes during Cryptosporidium infection. We demonstrated that silencing 66 of nucleoside-diphosphate kinase (NDK) drastically reduced invasion, proliferation and e...

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Section: Discussionsupporting

confidence: 66%

Gene silencing in Cryptosporidium: A rapid approach to identify novel targets for drug development

Castellanos-González

Martinez-Traverso

et al. 2019

Preprint

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“…In bonobos, five of these genes are, according to the literature, involved in female reproduction: ABCA13 (Nymoen et al. 2015), ESPL1 (Gurvits et al. 2017), KIF14 (Singel et al.…”

Section: Resultsmentioning

confidence: 99%

Genetic Variation in Pan Species Is Shaped by Demographic History and Harbors Lineage-Specific Functions

Han

Andrés

Kuhlwilm

2019

Genome Biology and Evolution

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Chimpanzees ( Pan troglodytes ) and bonobos ( Pan paniscus ) are the closest living relatives of humans, but the two species show distinct behavioral and physiological differences, particularly regarding female reproduction. Despite their recent rapid decline, the demographic histories of the two species have been different during the past 1–2 Myr, likely having an impact on their genomic diversity. Here, we analyze the inferred functional consequences of genetic variation across 69 individuals, making use of the most complete data set of genomes in the Pan clade to date. We test to which extent the demographic history influences the efficacy of purifying selection in these species. We find that small historical effective population sizes ( N e ) correlate not only with low levels of genetic diversity but also with a larger number of deleterious alleles in homozygosity and an increased proportion of deleterious changes at low frequencies. To investigate the putative genetic basis for phenotypic differences between chimpanzees and bonobos, we exploit the catalog of putatively deleterious protein-coding changes in each lineage. We show that bonobo-specific nonsynonymous changes are enriched in genes related to age at menarche in humans, suggesting that the prominent physiological differences in the female reproductive system between chimpanzees and bonobos might be explained, in part, by putatively adaptive changes on the bonobo lineage.

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“…To investigate the mechanism of anticryptosporidial activity, we evaluated expression proliferation (separine) and apoptosis markers (metacaspase) in the parasite. We found a down-regulation of separine expression (also known as separase), which is implicated in chromatin regulation during meiosis and mitosis processes 27 . This finding suggested that EA may be blocking proliferation through NDK inhibition, as found in the silencing experiments.…”

Section: Discussionmentioning

confidence: 82%

Systematic gene silencing identified Cryptosporidium nucleoside diphosphate kinase and other molecules as targets for suppression of parasite proliferation in human intestinal cells

Castellanos-González

Martinez-Traverso

et al. 2019

Sci Rep

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Cryptosporidiosis is a major cause of diarrheal disease. The only drug approved for cryptosporidiosis has limited efficacy in high-risk populations. Therefore novel drugs are urgently needed. We have identified several enzymes as potential targets for drug development and we have optimized a rapid method to silence genes in Cryptosporidium . In this study, we knocked down expression of the four selected genes: Actin (Act), Apicomplexan DNA-binding protein (Ap2), Rhomboid protein 1 (Rom 1), and nucleoside diphosphate kinase (NDK). After gene silencing, we evaluated the role of each target on parasite development using in vitro models of excystation, invasion, proliferation, and egress. We showed that silencing of Act, Ap2, NDK, and Rom1 reduced invasion, proliferation, and egress of Cryptosporidium . However, silencing of NDK markedly inhibited Cryptosporidium proliferation (~70%). We used an infection model to evaluate the anticryptosporidial activity of ellagic acid (EA), an NDK inhibitor. We showed that EA (EC50 = 15–30 µM) reduced parasite burden without showing human cell toxicity. Here, we demonstrated the usefulness of a rapid silencing method to identify novel targets for drug development. Because EA is a dietary supplement already approved for human use, this compound should be studied as a potential treatment for cryptosporidiosis.

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Separase is a marker for prognosis and mitotic activity in breast cancer

Cited by 25 publications

References 42 publications

Gene silencing in Cryptosporidium: A rapid approach to identify novel targets for drug development

Gene silencing in Cryptosporidium: A rapid approach to identify novel targets for drug development

Genetic Variation in Pan Species Is Shaped by Demographic History and Harbors Lineage-Specific Functions

Systematic gene silencing identified Cryptosporidium nucleoside diphosphate kinase and other molecules as targets for suppression of parasite proliferation in human intestinal cells

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