Functional studies of TcRjl, a novel GTPase of Trypanosoma cruzi , reveals phenotypes related with MAPK activation during parasite differentiation and after heterologous expression in Drosophila model system

Santos, Guilherme Rodrigo Reis Monteiro dos; Fontenele, Marcio; Dias, Felipe de Almeida; Oliveira, Pedro L.; Nepomuceno-Silva, José Luciano; Melo, Luiz Dione Barbosa de; Araujo, Helena; Lopes, Ulisses Gazos

doi:10.1016/j.bbrc.2015.09.110

Cited by 8 publications

(6 citation statements)

References 37 publications

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“…Other studies [ 54 ] had shown that ERK inhibits the expression of SREBP-1c in the model of nonalcoholic fatty liver induced by high-fat diet, and the MEK/ERK pathway played an important role in SREBP-1c expression induced by high-fat diet in NAFLD rats. In hepatoma cells, the ERK signaling pathway could reduce intracellular reactive oxygen species by inhibiting the expression of SREBP-1c [ 55 ], while in HACAT cells, the ERK inhibitor (PD98059) had no effect on the expression of SREBP-1c [ 56 ]. In our study, the expression of SREBP-1c was not significantly changed between the inhibitor group and the NaAsO 2 group.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Mechanism of Hepatic Lipid Metabolism Disorder Caused by NaAsO2 through Regulating the ERK/PPAR Signaling Pathway

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Chronic arsenic exposure is a risk factor for human fatty liver disease, and the ERK signaling pathway plays an important role in the regulation of liver lipid metabolism. However, whether ERK plays a role in the progression of arsenic-induced liver lipid metabolism disorder and the specific mechanism remain unclear. Here, by constructing a rat model of liver lipid metabolism disorder induced by chronic arsenic exposure, we demonstrated that ERK might regulate arsenic-induced liver lipid metabolism disorders through the PPAR signaling pathway. Arsenic could upregulate the expression of PPARγ and CD36 in the rat liver, decrease the expression of PPARα and CPT-1 in the rat liver, increase the organ coefficient of the rat liver, decrease the content of TG in rat serum, and promote fat deposition in the rat liver. In the arsenic-induced rat model of hepatic lipid metabolism disorder, we found that the expression of p-ERK was increased. In order to further explore whether the ERK signaling pathway was involved in arsenic-induced liver lipid metabolism disorder, we exposed L-02 cells to different arsenic concentrations, and the results showed that arsenic significantly increased the expression of P-ERK in L-02 cells in a dose-dependent manner. We further treated L-02 cells with ERK inhibitors and found that the expression of TG, PPARα, and CPT-1 in L-02 cells increased, while the expression of P-ERK, PPARγ, and CD36 decreased. In conclusion, ERK may be involved in arsenic-induced liver lipid metabolism disorder by regulating the PPAR signaling pathway. These findings are expected to provide a new targeting strategy for arsenic-induced liver lipid metabolism disorder.

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Section: Discussionmentioning

confidence: 99%

The Molecular Mechanism of Hepatic Lipid Metabolism Disorder Caused by NaAsO2 through Regulating the ERK/PPAR Signaling Pathway

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Multiple signaling pathways, such as the MAPK, AKT, and NF‐κB pathways, are connected by complex networks in eukaryotic cells, including ECs, and control gene expression, cell survival, apoptosis, and cell differentiation [35–38]. Notably, our results showed that MAPK4 silencing did not affect the AKT, JNK, and NF‐κB signaling pathways in ECs.…”

Section: Discussionmentioning

confidence: 76%

MAPK4 facilitates angiogenesis by inhibiting the ERK pathway in non‐small cell lung cancer

Chen,

Yang,

Liu

et al. 2024

Cancer Innovation

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BackgroundAngiogenesis plays an important role in the occurrence and development of non‐small cell lung cancer (NSCLC). The atypical mitogen‐activated protein kinase 4 (MAPK4) has been shown to be involved in the pathogenesis of various diseases. However, the potential role of MAPK4 in the tumor angiogenesis of NSCLC remains unclear.MethodsAdult male C57BL/6 wild‐type mice were randomly divided into the control group and p‐siMAPK4 intervention group, respectively. The cell proliferation was analyzed with flow cytometry and immunofluorescence staining. The vascular density in tumor mass was analyzed by immunofluorescence staining. The expressions of MAPK4 and related signaling molecules were detected by western blot analysis and immunofluorescence staining, and so on.ResultsWe found that the expression of MAPK4, which was dominantly expressed in local endothelial cells (ECs), was correlated with tumor angiogenesis of NSCLC. Furthermore, MAPK4 silencing inhibited the proliferation and migration abilities of human umbilical vein ECs (HUVECs). Global gene analysis showed that MAPK4 silencing altered the expression of multiple genes related to cell cycle and angiogenesis pathways, and that MAPK4 silencing increased transduction of the extracellular regulated protein kinases 1/2 (ERK1/2) pathway but not Akt and c‐Jun n‐terminal kinase pathways. Further analysis showed that MAPK4 silencing inhibited the proliferation and migration abilities of HUVECs cultured in tumor cell supernatant, which was accompanied with increased transduction of the ERK1/2 pathway. Clinical data analysis suggested that the higher expression of MAPK4 and CD34 were associated with poor prognosis of patients with NSCLC. Targeted silencing of MAPK4 in ECs using small interfering RNA driven by the CD34 promoter effectively inhibited tumor angiogenesis and growth of NSCLC in vivo.ConclusionOur results reveal that MAPK4 plays an important role in the angiogenesis and development of NSCLC. MAPK4 may thus represent a new target for NSCLC.

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Section: Discussionmentioning

confidence: 99%

“…For example, two of the converging alleles affected distinct members of the Ras GTPase family and thus a signaling pathway known to regulate eukaryotic cell growth, division and differentiation [49]. Indeed, Ras GTPases have been linked to cell proliferation and differentiation in Trypanosoma cruzi [50, 51], microtubule biogenesis and cytokinesis in T. brucei [52] and their survival during tse tse fly infection [53]. Significantly, in L. donovani , a non-synonymous SNV in the Ras-like small GTPase-RagC (LdBPK_366140.1) affects tissue tropism [15], indicating that a single SNV may produce important phenotypic change during infection.…”

Section: Discussionmentioning

confidence: 99%

Leishmania allelic selection during experimental sand fly infection correlates with mutational signatures of oxidative DNA damage

Bussotti

Pescher

et al. 2022

Preprint

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Trypanosomatid pathogens are transmitted by blood-feeding insects, causing devastating human infections. Survival of these parasites in their vertebrate and invertebrate hosts relies on their capacity to differentiate into distinct stages that are the result of a co-evolutionary process. These stages show in addition important phenotypic shifts that often impacts infection, affecting for example parasite pathogenicity, tissue tropism, or drug susceptibility. Despite their clinical relevance, the evolutionary mechanisms that allow for the selection of such adaptive phenotypes remain only poorly investigated. Here we use Leishmania donovani as a trypanosomatid model pathogen to shed first light on parasite evolutionary adaptation during experimental sand fly infection. Applying a comparative genomics approach on hamster-isolated amastigotes and derived promastigotes before (input) and after (output) infection of Phlebotomus orientalis revealed a strong bottleneck effect on the parasite population as judged by principal component and phylogenetic analyses of input and output parasite DNA sequences. Despite random genetic drift caused by the bottleneck effect, our analyses revealed various genomic signals that seem under positive selection given their convergence between independent biological replicates. While no significant fluctuations in gene copy number were revealed between input and output parasites, convergent selection was observed for karyotype, haplotype and allelic changes during sand fly infection. Our analyses further uncovered signature mutations of oxidative DNA damage in the output parasite genomes, suggesting that Leishmania suffers from oxidative stress inside the insect digestive tract. Our results propose a new model of Leishmania genomic adaptation during sand fly infection, where oxidative DNA damage and DNA repair processes drive haplotype and allelic selection. The experimental and computational framework presented here provides a useful blueprint to assess evolutionary adaptation of other eukaryotic pathogens inside their insect vectors, such as Plasmodium spp, Trypanosoma brucei and Trypanosoma cruzi.

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Functional studies of TcRjl, a novel GTPase of Trypanosoma cruzi , reveals phenotypes related with MAPK activation during parasite differentiation and after heterologous expression in Drosophila model system

Cited by 8 publications

References 37 publications

The Molecular Mechanism of Hepatic Lipid Metabolism Disorder Caused by NaAsO2 through Regulating the ERK/PPAR Signaling Pathway

The Molecular Mechanism of Hepatic Lipid Metabolism Disorder Caused by NaAsO2 through Regulating the ERK/PPAR Signaling Pathway

MAPK4 facilitates angiogenesis by inhibiting the ERK pathway in non‐small cell lung cancer

Leishmania allelic selection during experimental sand fly infection correlates with mutational signatures of oxidative DNA damage

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