Antineoplastic effect of compounds C14 and P8 on TNBC and radioresistant TNBC cells by stabilizing the K-Ras4B/PDE6δ complex.

Introduction: Breast cancer (BC) is the leading cause of cancer-related deaths among women, with triple-negative breast cancer (TNBC) representing one of the most aggressive and treatment-resistant subtypes. In this study, we aimed to evaluate the antitumor potential of C14 and P8 molecules in both TNBC and radioresistant TNBC cells. These compounds were chosen for their ability to stabilize the complex formed by the overactivated form of K-Ras4B and its membrane transporter (PDE6δ).

Circulating miRNAs as Noninvasive Biomarkers for PDAC Diagnosis and Prognosis in Mexico.

Among malignant neoplasms, pancreatic ductal adenocarcinoma (PDAC) has one of the highest fatality rates due to its late detection. Therefore, it is essential to discover a noninvasive, early, specific, and sensitive diagnostic method. MicroRNAs (miRNAs) are attractive biomarkers because they are accessible, highly specific, and sensitive.

Synergistic effect of antagonists to KRas4B/PDE6 molecular complex in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among all human cancers as it is highly resistant to chemotherapy. K-Ras mutations usually trigger the development and progression of PDAC. We hypothesized that compounds stabilizing the KRas4B/PDE6δ complex could serve as PDAC treatments.

Interplay Between the Histone Variant H2A.Z and the Epigenome in Pancreatic Cancer.

Background: The oncogenic process is orchestrated by a complex network of chromatin remodeling elements that shape the cancer epigenome. Histone variant H2A.Z regulates DNA control elements such as promoters and enhancers in different types of cancer; however, the interplay between H2A.

In Silico Identification and Characterization of circRNAs as Potential Virulence-Related miRNA/siRNA Sponges from and Encystment-Related circRNAs from .

Ubiquitous eukaryotic non-coding circular RNAs regulate transcription and translation. We have reported full-length intronic circular RNAs (flicRNAs) in with esterified 3'ss and 5'ss. Their 5'ss GU-rich elements are essential for their biogenesis and their suggested role in transcription regulation.

I-C19 Iodide Radioisotope and Synthetic I-C19 Compounds as K-Ras4B-PDE6δ Inhibitors: A Novel Approach against Colorectal Cancer-Biological Characterization, Biokinetics and Dosimetry.

In 40-50% of colorectal cancer (CRC) cases, K-Ras gene mutations occur, which induce the expression of the K-Ras4B oncogenic isoform. K-Ras4B is transported by phosphodiesterase-6δ (PDE6δ) to the plasma membrane, where the K-Ras4B-PDE6δ complex dissociates and K-Ras4B, coupled to the plasma membrane, activates signaling pathways that favor cancer aggressiveness. Thus, the inhibition of the K-Ras4B-PDE6δ dissociation using specific small molecules could be a new strategy for the treatment of patients with CRC.

p21-Activated Kinase 1 Promotes Breast Tumorigenesis Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II.

p21-Activated kinase-1 (Pak1) is frequently overexpressed and/or amplified in human breast cancer and is necessary for transformation of mammary epithelial cells. Here, we show that Pak1 interacts with and phosphorylates the Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), and that pharmacological inhibition or depletion of Pak1 leads to diminished activity of CaMKII. We found a strong correlation between Pak1 and CaMKII expression in human breast cancer samples, and combined inhibition of Pak1 and CaMKII with small-molecule inhibitors was synergistic and induced apoptosis more potently in Her2 positive and triple negative breast cancer (TNBC) cells.

A class I histone deacetylase is implicated in the encystation of Entamoeba invadens.

Epigenetic mechanisms such as histone acetylation and deacetylation participate in regulation of the genes involved in encystation of Entamoeba invadens. However, the histones and target residues involved, and whether the acetylation and deacetylation of the histones leads to the regulation of gene expression associated with the encystation of this parasite, remain unknown. In this study, we found that E.

The activity of Aurora kinase B is required for dengue virus release.

Flaviviruses, such as Dengue (DENV), Zika, Yellow Fever, Japanese Encephalitis and West Nile are important pathogens with high morbidity and mortality. The last estimation indicates that ∼390 millions of people are infected by DENV per year. The DENV replicative cycle occurs mainly in the cytoplasm of the infected cells and different cytoplasmic, nuclear and mitochondrial proteins participate in viral replication.

Clipped histone H3 is integrated into nucleosomes of DNA replication genes in the human malaria parasite .

Post-translational modifications of histone H3 N-terminal tails are key epigenetic regulators of virulence gene expression and sexual commitment in the human malaria parasite Here, we identify proteolytic clipping of the N-terminal tail of nucleosome-associated histone H3 at amino acid position 21 as a new chromatin modification. A cathepsin C-like proteolytic clipping activity is observed in nuclear parasite extracts. Notably, an ectopically expressed version of clipped histone H3, PfH3p-HA, is targeted to the nucleus and integrates into mononucleosomes.

KRas4B-PDE6δ complex stabilization by small molecules obtained by virtual screening affects Ras signaling in pancreatic cancer.

Background: The GTPase KRas4B has been utilized as a principal target in the development of anticancer drugs. PDE6δ transports KRas4B to the plasma membrane, where it is released to activate various signaling pathways required for the initiation and maintenance of cancer. Therefore, identifying new small molecules that prevent activation of this GTPase by stabilizing the KRas4B-PDE6δ molecular complex is a practical strategy to fight against cancer.

The small organic molecule C19 binds and strengthens the KRAS4b-PDEδ complex and inhibits growth of colorectal cancer cells in vitro and in vivo.

Background: Colorectal cancer is the third most common cancer worldwide; and in 40% of all cases, KRAS4b-activating mutations occur. KRAS4b is transported by phosphodiesterase-6δ (PDEδ) to the plasma membrane, where it gets activated. PDEδ downregulation prevents redistribution and activation of KRAS4b.

PfAP2Tel, harbouring a non-canonical DNA-binding AP2 domain, binds to Plasmodium falciparum telomeres.

The telomeres of the malaria parasite Plasmodium falciparum are essential not only for chromosome end maintenance during blood stage development in humans but also to generate genetic diversity by facilitating homologous recombination of subtelomeric, multigene virulence families such as var and rifin. However, other than the telomerase PfTERT, proteins that act at P. falciparum telomeres are poorly characterised.

Maf1 is a negative regulator of transcription in Trypanosoma brucei.

RNA polymerase III (Pol III) produces small RNA molecules that play essential roles in mRNA processing and translation. Maf1, originally described as a negative regulator of Pol III transcription, has been studied from yeast to human. Here we characterized Maf1 in the parasitic protozoa Trypanosoma brucei (TbMaf1), representing the first report to analyse Maf1 in an early-diverged eukaryote.

A new nucleocytoplasmic RhoGAP protein contributes to control the pathogenicity of Entamoeba histolytica by regulating EhRacC and EhRacD activity.

Small GTPases are signalling molecules that regulate important cellular processes. GTPases are deactivated by GTPase-activating proteins (GAPs). While human GAPs have been intensively studied, no GAP has yet been characterized in Entamoeba histolytica.

Associations between whole peripheral blood fatty acids and DNA methylation in humans.

Fatty acids (FA) modify DNA methylation in vitro, but limited information is available on whether corresponding associations exist in vivo and reflect any short-term effect of the diet. Associations between global DNA methylation and FAs were sought in blood from lactating infants (LI; n = 49) and adult males (AMM; n = 12) equally distributed across the three conventional BMI classes. AMM provided multiple samples at 2-hour intervals during 8 hours after either a single Western diet-representative meal (post-prandial samples) or no meal (fasting samples).

Detection of beta-tubulin in the cytoplasm of the interphasic Entamoeba histolytica trophozoites.

It is known that the microtubules (MT) of Entamoeba histolytica trophozoites form an intranuclear mitotic spindle. However, electron microscopy studies and the employment of anti-beta-tubulin (β-tubulin) antibodies have not exhibited these cytoskeletal structures in the cytoplasm of these parasites. The purpose of this work was to detect β-tubulin in the cytoplasm of interphasic E.

Ribosomal RNA Genes in the Protozoan Parasite Leishmania major Possess a Nucleosomal Structure.

Little is known about nucleosome structure and epigenetic regulation of transcription of rRNA genes in early-branched eukaryotes. Here we analyze the chromatin architecture and distribution of some histone modifications in the rRNA genes in the parasitic protozoon Leishmania major. Southern blots of MNase-partially-digested chromatin with DNA probes spanning the whole rRNA gene repeat showed that the intergenic spacer presents a tight nucleosomal structure, whereas the promoter region is practically devoid of nucleosomes.

Identification of repressive and active epigenetic marks and nuclear bodies in Entamoeba histolytica.

Background: In human hosts, Entamoeba histolytica cysts can develop into trophozoites, suggesting that the life cycle of this parasite are regulated by changes in gene expression. To date, some evidence has suggested that epigenetic mechanisms such as DNA methylation and histone modification are involved in the regulation of gene expression in Entamoeba. Some post-translational modifications (PTMs) at the N-terminus of E.

Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura.

NF-κB essential modulator (NEMO) is a component of the IKK complex, which participates in the activation of the NF-κB pathway. Hypomorphic mutations in the IKBKG gene result in different forms of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males without affecting carrier females. Here, we describe a hypomorphic and missense mutation, designated c.

The selenocysteine tRNA gene in leishmania major is transcribed by both RNA polymerase II and RNA polymerase III.

Eukaryotic tRNAs, transcribed by RNA polymerase III (Pol III), contain boxes A and B as internal promoter elements. One exception is the selenocysteine (Sec) tRNA (tRNA-Sec), whose transcription is directed by an internal box B and three extragenic sequences in vertebrates. Here we report on the transcriptional analysis of the tRNA-Sec gene in the protozoan parasite Leishmania major.

The Plasmodium falciparum translationally controlled tumor protein (TCTP) is incorporated more efficiently into B cells than its human homologue.

Plasmodium falciparum secretes a homologue of the translationally controlled tumor protein (TCTP) into serum of infected individuals, although its role in pathogenesis or virulence is unknown. To determine the effect of P. falciparum TCTP on B cells as compared to human TCTP, fluorescently labeled proteins were incubated on primary cultures of mouse splenic B cells and analyzed by flow cytometry and confocal microscopy.

Impact of chromosome ends on the biology and virulence of Plasmodium falciparum.

In recent years, many studies have focused on heterochromatin located at chromosome ends, which plays an important role in regulating gene expression in many organisms ranging from yeast to humans. Similarly, in the protozoan Plasmodium falciparum, which is the most virulent human malaria parasite, the heterochromatin present in telomeres and subtelomeric regions exerts a silencing effect on the virulence gene families located therein. Studies addressing P.

Two long non-coding RNAs generated from subtelomeric regions accumulate in a novel perinuclear compartment in Plasmodium falciparum.

Chromosome ends have been implicated in the default silencing of clonally variant gene families in the human malaria parasite Plasmodium falciparum. These chromosome regions are organized into heterochromatin, as defined by the presence of a repressive histone H3 lysine 9 trimethylated marker and heterochromatin protein 1. Here, we show that the non-coding subtelomeric region adjacent to virulence genes forms facultative heterochromatin in a cell cycle-dependent manner.

PfAlbas constitute a new eukaryotic DNA/RNA-binding protein family in malaria parasites.

In Plasmodium falciparum, perinuclear subtelomeric chromatin conveys monoallelic expression of virulence genes. However, proteins that directly bind to chromosome ends are poorly described. Here we identify a novel DNA/RNA-binding protein family that bears homology to the archaeal protein Alba (Acetylation lowers binding affinity).