scholarly journals AML1/ETO and its function as a regulator of gene transcription via epigenetic mechanisms

Oncogene ◽  
2021 ◽  
Author(s):  
Kai Rejeski ◽  
Jesús Duque-Afonso ◽  
Michael Lübbert
Keyword(s):  
Gene Transcription ◽  
Protein Function ◽  
Structural Changes ◽  
Target Genes ◽  
Chromosomal Translocation ◽  
Global Changes ◽  
Cellular Processes ◽  
Genetic Landscape ◽  
Specific Impact

AbstractThe chromosomal translocation t(8;21) and the resulting oncofusion gene AML1/ETO have long served as a prototypical genetic lesion to model and understand leukemogenesis. In this review, we describe the wide-ranging role of AML1/ETO in AML leukemogenesis, with a particular focus on the aberrant epigenetic regulation of gene transcription driven by this AML-defining mutation. We begin by analyzing how structural changes secondary to distinct genomic breakpoints and splice changes, as well as posttranscriptional modifications, influence AML1/ETO protein function. Next, we characterize how AML1/ETO recruits chromatin-modifying enzymes to target genes and how the oncofusion protein alters chromatin marks, transcription factor binding, and gene expression. We explore the specific impact of these global changes in the epigenetic network facilitated by the AML1/ETO oncofusion on cellular processes and leukemic growth. Furthermore, we define the genetic landscape of AML1/ETO-positive AML, presenting the current literature concerning the incidence of cooperating mutations in genes such as KIT, FLT3, and NRAS. Finally, we outline how alterations in transcriptional regulation patterns create potential vulnerabilities that may be exploited by epigenetically active agents and other therapeutics.

MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target

2020 ◽  
Vol 26 ◽  
Author(s):  
Yini Ma ◽  
Xiu Cao ◽  
Guojuan Shi ◽  
Tianlu Shi
Keyword(s):  
Digestive System ◽  
Target Genes ◽  
Malignant Neoplasm ◽  
Vital Role ◽  
Diagnostic Biomarkers ◽  
Cellular Processes ◽  
Promising Therapeutic Target ◽  
Direct Target ◽  
Potential Strategy

: MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles for cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as valuable biomarkers for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.

scholarly journals Trimethyllysine: From Carnitine Biosynthesis to Epigenetics

2020 ◽  
Vol 21 (24) ◽  
pp. 9451
Author(s):  
Marijn N. Maas ◽  
Jordi C. J. Hintzen ◽  
Miriam R. B. Porzberg ◽  
Jasmin Mecinović
Keyword(s):  
Protein Function ◽  
Genetic Disorders ◽  
Enzymatic Reactions ◽  
Lysine Methylation ◽  
Nucleosome Assembly ◽  
Cellular Processes ◽  
Subsequent Effect ◽  
Control Protein ◽  
Epigenetic Processes

Trimethyllysine is an important post-translationally modified amino acid with functions in the carnitine biosynthesis and regulation of key epigenetic processes. Protein lysine methyltransferases and demethylases dynamically control protein lysine methylation, with each state of methylation changing the biophysical properties of lysine and the subsequent effect on protein function, in particular histone proteins and their central role in epigenetics. Epigenetic reader domain proteins can distinguish between different lysine methylation states and initiate downstream cellular processes upon recognition. Dysregulation of protein methylation is linked to various diseases, including cancer, inflammation, and genetic disorders. In this review, we cover biomolecular studies on the role of trimethyllysine in carnitine biosynthesis, different enzymatic reactions involved in the synthesis and removal of trimethyllysine, trimethyllysine recognition by reader proteins, and the role of trimethyllysine on the nucleosome assembly.

scholarly journals Dr. Jekyll and Mr. Hyde: The Two Faces of the FUS/EWS/TAF15 Protein Family

Sarcoma ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Heinrich Kovar
Keyword(s):  
Protein Function ◽  
Target Genes ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Fusion Gene ◽  
Tumor Biology ◽  
Central Function ◽  
Epithelial Cancers ◽  
Transcription Factor Genes

FUS, EWS, and TAF15 form the FET family of RNA-binding proteins whose genes are found rearranged with various transcription factor genes predominantly in sarcomas and in rare hematopoietic and epithelial cancers. The resulting fusion gene products have attracted considerable interest as diagnostic and promising therapeutic targets. So far, oncogenic FET fusion proteins have been regarded as strong transcription factors that aberrantly activate or repress target genes of their DNA-binding fusion partners. However, the role of the transactivating domain in the context of the normal FET proteins is poorly defined, and, therefore, our knowledge on how FET aberrations impact on tumor biology is incomplete. Since we believe that a full understanding of aberrant FET protein function can only arise from looking at both sides of the coin, the good and the evil, this paper summarizes evidence for the central function of FET proteins in bridging RNA transcription, processing, transport, and DNA repair.

scholarly journals Aggregation is a Context-Dependent Constraint on Protein Evolution

2021 ◽  
Vol 8 ◽  
Author(s):  
Michele Monti ◽  
Alexandros Armaos ◽  
Marco Fantini ◽  
Annalisa Pastore ◽  
Gian Gaetano Tartaglia
Keyword(s):  
Molecular Evolution ◽  
Protein Evolution ◽  
Protein Function ◽  
Beta Lactamase ◽  
Data Set ◽  
Cellular Processes ◽  
Bacterial Enzyme ◽  
Rna Biogenesis ◽  
Context Dependent

Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution. In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed in E. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function. Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in the cell.

Peptidomics analysis of potato protein hydrolysates: post-translational modifications and peptide hydrophobicity

2017 ◽  
Author(s):  
Shixiang Yao ◽  
Chibuike Udenigwe
Keyword(s):  
Protein Function ◽  
Structural Changes ◽  
Protein Hydrolysates ◽  
Proteolytic Processing ◽  
Methionine Oxidation ◽  
Potato Protein ◽  
Post Translational Modifications ◽  
Peptide Hydrophobicity ◽  
Proteins And Peptides

Post-translational modifications (PTMs) often <a></a><a>occur in proteins</a> and play a regulatory role in protein function. However, the role of PTMs in food-derived peptides remains largely unknown. The shotgun peptidomics strategy was employed to identify PTMs in peptides from potato protein hydrolysates. Various hydrophobicity-inducing PTMs were found to be located in different potato peptides, <i>e.g</i>. acetylation of lysine, N-terminal of proteins and peptides, C-terminal amidation, asparagine/glutamine deamidaiton, methylation and trimethylation, methionine oxidation, and N-terminal pyro-glutamate formation. Some of the PTMs are likely formed by chemical reactions that occur during isolation and proteolytic processing of potato proteins. The PTMs enhance peptide hydrophobicity, which can improve bioactivity, decrease solubility and increase the bitterness of peptides. This is the first report that food-derived peptides are widely modified by various PTMs associated with hydrophobicity-inducing structural changes. This finding will enhance understanding of the behaviour of bioactive peptides in biological matrices.

scholarly journals The MicroRNA Family Both in Normal Development and in Different Diseases: The miR-17-92 Cluster

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaodan Bai ◽  
Shengyu Hua ◽  
Junping Zhang ◽  
Shixin Xu
Keyword(s):  
Small Molecules ◽  
Target Genes ◽  
Normal Development ◽  
Neurological Diseases ◽  
Multiple Target ◽  
Cellular Processes ◽  
Microrna Family ◽  
Mirna Clusters ◽  
And Function

An increasing number of research studies over recent years have focused on the function of microRNA (miRNA) molecules which have unique characteristics in terms of structure and function. They represent a class of endogenous noncoding single-strand small molecules. An abundance of miRNA clusters has been found in the genomes of various organisms often located in a polycistron. The miR-17-92 family is among the most famous miRNAs and has been identified as an oncogene. The functions of this cluster, together with the seven individual molecules that it comprises, are most related to cancers, so it would not be surprising that they are considered to have involvement in the development of tumors. The miR-17-92 cluster is therefore expected not only to be a tumor marker, but also to perform an important role in the early diagnosis of those diseases and possibly also be a target for tumor biotherapy. The miR-17-92 cluster affects the development of disease by regulating many related cellular processes and multiple target genes. Interestingly, it also has important roles that cannot be ignored in disease of the nervous system and circulation and modulates the growth and development of bone. Therefore, it provides new opportunities for disease prevention, clinical diagnosis, prognosis, and targeted therapy. Here we review the role of the miR-17-92 cluster that has received little attention in relation to neurological diseases, cardiac diseases, and the development of bone and tumors.

The role of Bni5 in the regulation of septin higher-order structure formation

2015 ◽  
Vol 396 (12) ◽  
pp. 1325-1337 ◽  
Author(s):  
Csilla Patasi ◽  
Jana Godočíková ◽  
Soňa Michlíková ◽  
Yan Nie ◽  
Radka Káčeriková ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Structural Changes ◽  
Higher Order ◽  
Cytoskeletal Proteins ◽  
Order Structure ◽  
Division Plane ◽  
Cellular Processes ◽  
Order Structures

Abstract Septins are a family of conserved cytoskeletal proteins playing an essential role in cytokinesis and in many other cellular processes in fungi and animals. In budding yeast Saccharomyces cerevisiae, septins form filaments and higher-order structures at the mother-bud neck depending on the particular stage of the cell cycle. Septin structures at the division plane serve as a scaffold to recruit the proteins required for particular cellular processes. The formation and localization of septin structures at particular stages of the cell cycle also determine functionality of these proteins. Many different proteins participate in regulating septin assembly. Despite recent developments, we are only beginning to understand how specific protein-protein interactions lead to changes in the polymerization of septin filaments or assembly of higher-order structures. Here, using fluorescence and electron microscopy, we found that Bni5 crosslinks septin filaments into networks by bridging pairs or multiple filaments, forming structures that resemble railways. Furthermore, Bni5 appears to be a substrate of the Elm1 protein kinase in vitro. Moreover, Elm1 induces in the presence of Bni5 disassembly of long septin filaments, suggesting that these proteins may participate in the hourglass to double ring transition. This work gives new insight into the regulatory role of Bni5 in the structural changes of septins.

MicroRNA 299-3p modulates replicative senescence in endothelial cells

2013 ◽  
Vol 45 (7) ◽  
pp. 256-267 ◽  
Author(s):  
Hui-Lan Jong ◽  
Mohd Rais Mustafa ◽  
Paul M. Vanhoutte ◽  
Sazaly AbuBakar ◽  
Pooi-Fong Wong
Keyword(s):  
Endothelial Cells ◽  
Target Genes ◽  
Replicative Senescence ◽  
Umbilical Vein ◽  
Gene Profiling ◽  
Cellular Processes ◽  
Migration Capacity ◽  
Umbilical Vein Endothelial Cells ◽  
Insight Into

MicroRNAs (miRNAs) regulate various cellular processes. While several genes associated with replicative senescence have been described in endothelial cells, miRNAs that regulate these genes remain largely unknown. The present study was designed to identify miRNAs associated with replicative senescence and their target genes in human umbilical vein endothelial cells (HUVECs). An integrated miRNA and gene profiling approach revealed that hsa-miR-299-3p is upregulated in senescent HUVECs compared with the young cells, and one of its target genes could be IGF1. IGF1 was upregulated in senescent compared with young HUVECs, and knockdown of hsa-miR-299-3p dose-dependently increased the mRNA expression of IGF1, more significantly observed in the presenescent cells ( passage 19) compared with the senescent cells ( passage 25). Knockdown of hsa-miR-299-3p also resulted in significant reduction in the percentage of cells positively stained for senescence-associated β-galactosidase and increases in cell viability measured by MTT assay but marginal increases in cell proliferation and cell migration capacity measured by real-time growth kinetics analysis. Moreover, knockdown of hsa-miR-299-3p also increased proliferation of cells treated with H2O2 to induce senescence. These findings suggest that hsa-miR-299-3p may delay or protect against replicative senescence by improving the metabolic activity of the senesced cells but does not stimulate growth of the remaining cells in senescent cultures. Hence, these findings provide an early insight into the role of hsa-miR-299-3p in the modulation of replicative senescence in HUVECs.

scholarly journals Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

2021 ◽  
Vol 14 (9) ◽  
pp. 848
Author(s):  
Lucas Cruz ◽  
Paula Soares ◽  
Marcelo Correia
Keyword(s):  
Protein Function ◽  
Deubiquitinating Enzymes ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Cellular Targets ◽  
Cellular Processes ◽  
Protein Ubiquitination ◽  
Damage Repair ◽  
Ubiquitin Molecule

Ubiquitination represents a post-translational modification (PTM) essential for the maintenance of cellular homeostasis. Ubiquitination is involved in the regulation of protein function, localization and turnover through the attachment of a ubiquitin molecule(s) to a target protein. Ubiquitination can be reversed through the action of deubiquitinating enzymes (DUBs). The DUB enzymes have the ability to remove the mono- or poly-ubiquitination signals and are involved in the maturation, recycling, editing and rearrangement of ubiquitin(s). Ubiquitin-specific proteases (USPs) are the biggest family of DUBs, responsible for numerous cellular functions through interactions with different cellular targets. Over the past few years, several studies have focused on the role of USPs in carcinogenesis, which has led to an increasing development of therapies based on USP inhibitors. In this review, we intend to describe different cellular functions, such as the cell cycle, DNA damage repair, chromatin remodeling and several signaling pathways, in which USPs are involved in the development or progression of cancer. In addition, we describe existing therapies that target the inhibition of USPs.

scholarly journals A STUDY OF THE ROLE OF MICRORNA IN PITUITARY ADENOMA

2018 ◽  
Vol 5 (2) ◽  
pp. 8-15
Author(s):  
I. F. Gareev ◽  
O. A. Beylerli
Keyword(s):  
Pituitary Adenoma ◽  
Target Genes ◽  
Decisive Role ◽  
Cellular Processes ◽  
New Class ◽  
Number Of Genes ◽  
Non Coding Rnas ◽  
New Biomarkers ◽  
New Evidence

MicroRNAs are a new class of small non-coding RNAs, a length of 18–22 nucleotides that play a decisive role as posttranscriptional regulators of gene expression. Due to the large number of genes, regulated microRNAs, microRNAs are involved in many cellular processes. The study of the impairment of the expression of the target genes of microRNA, often associated with changes in important biological characteristics, provides a significant understanding of the role of microRNAs in oncogenesis. New evidence suggests that aberrant microRNA expression or dysregulation of endogenous microRNAs affects the onset and development of tumors, including adenomas of the pituitary gland. In this review, the significance of some microRNAs in the pathology of the pituitary adenoma will be assessed, as well as data on the study of microRNAs as therapeutic targets and new biomarkers.

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