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At least 1,081 records · Page 60Linked to original sources

PubMed2007

A morphologically conserved nonapoptotic program promotes linker cell death in Caenorhabditis elegans.

Apoptosis, cell death characterized by stereotypical morphological features, requires caspase proteases. Nonapoptotic, caspase-independent cell death pathways have been postulated; however, little is known about their molecular constituents or in vivo functions. Here, we show that death of the Caenorhabditis elegans linker cell during development is independent of the ced-3 caspase and all known cell death genes. The linker cell employs a cell-autonomous death program, and a previously undescribed engulfment program is required for its clearance. Dying linker cells display nonapoptotic features, including nuclear crenellation, absence of chromatin condensation, organelle swelling, and accumulation of cytoplasmic membrane-bound structures. Similar features are seen during developmental death of neurons in the vertebrate spinal cord and ciliary ganglia. Linker cell death is controlled by the microRNA let-7 and Zn-finger protein LIN-29, components of the C. elegans developmental timing pathway. We propose that the program executing linker cell death is conserved and used during vertebrate development.

Animals↗

PubMed2005

Dicing and slicing: the core machinery of the RNA interference pathway.

RNA interference (RNAi) is broadly defined as a gene silencing pathway that is triggered by double-stranded RNA (dsRNA). Many variations have been described on this theme. The dsRNA trigger can be supplied exogenously, as an experimental tool, or can derive from the genome in the form of microRNAs. Gene silencing can be the result of nucleolytic degradation of the mRNA, or by translational suppression. At the heart of the pathway are two ribonuclease machines. The ribonuclease III enzyme Dicer initiates the RNAi pathway by generating the active short interfering RNA trigger. Silencing is effected by the RNA-induced silencing complex and its RNaseH core enzyme Argonaute. This review describes the discovery of these machines and discusses future lines of work on this amazing biochemical pathway.

Animals↗

PubMed2006

The evolution and diversification of Dicers in plants.

Most multicellular organisms regulate developmental transitions by microRNAs, which are generated by an enzyme, Dicer. Insects and fungi have two Dicer-like genes, and many animals have only one, yet the plant, Arabidopsis, has four. Examining the poplar and rice genomes revealed that they contain five and six Dicer-like genes, respectively. Analysis of these genes suggests that plants require a basic set of four Dicer types which were present before the divergence of mono- and dicotyledonous plants ( approximately 200 million years ago), but after the divergence of plants from green algae. A fifth type of Dicer seems to have evolved in monocots.

Arabidopsis↗

PubMed2006

Mismatched siRNAs downregulate mRNAs as a function of target site location.

In mammalian cells, RNA interference can be mediated by synthetic duplex RNAs, termed small interfering RNAs (siRNAs), which assist in cleaving completely complementary mRNA transcripts. MicroRNAs (miRNAs) are endogenous small RNAs that assist in translationally repressing mRNAs with regions of partial complementarity, but may also reduce transcript levels. Since miRNAs predominantly interact with the 3' UTRs of transcripts, we sought to ask if mismatched siRNAs mimicking miRNAs affect cognate mRNA levels as a function of target site location. We find that mismatched siRNAs targeting the 3' UTRs of two endogenous transcripts yield a greater reduction in mRNA levels than those targeting the coding region. Our findings demonstrate the importance of target site location within endogenous mRNAs for small RNAs associated with RNAi.

ATP-Binding Cassette Transporters↗

PubMed2006

Mutants defective in a Mucor circinelloides dicer-like gene are not compromised in siRNA silencing but display developmental defects.

Dicer proteins are ribonuclease III enzymes that process double stranded RNA precursors into small RNAs categorized as small interfering RNAs (siRNAs) or microRNAs (miRNAs), which suppress gene expression through the RNA silencing mechanism. We have isolated a dicer-like gene (dcl-1) of Mucor circinelloides, the first gene of this family to be identified in zygomycetes. The dcl-1 mRNA occurred in multiple forms, including the truncated molecules that result from premature polyadenylation. Null dcl-1 mutants were not impaired as regards transgene-induced gene silencing, since they exhibited the same silencing frequency as the wild-type strain and accumulated the two size classes of siRNA associated with RNA silencing in M. circinelloides. However, dcl-1 mutants showed a reduced growth rate and a hyphal growth alteration, which suggests that the dcl-1 gene has some role in the control of endogenous functions.

Base Sequence↗

PubMed2006

Transcription, translation and fragile X syndrome.

The fragile X mental retardation protein (FMRP) plays a role in the control of local protein synthesis in the dendrites. Loss of its production in fragile X syndrome is associated with transcriptional dysregulation of the gene. Recent work demonstrates that Sp1 and NRF1 transcriptionally control this gene. Other studies reveal how the microRNA pathway and signaling are related to FMRP function through the metabotropic glutamate receptor. These studies provide new insights through which we can better understand the inactivation of the FMR1 gene and, in turn, the consequence of FMRP loss.

Animals↗

PubMed2005

Non-coding RNAs: new players in eukaryotic biology.

The completion of the human, mouse and other eukaryotic genomes were important scientific milestones, but they were just small steps towards the understanding of eukaryotic biology. Recent transcriptome analysis and different experimental approaches have identified a surprisingly large number of non-coding RNAs (ncRNAs) in eukaryotic cells. ncRNAs comprise microRNAs, anti-sense transcripts and other Transcriptional Units containing a high density of stop codons and lacking any extensive "Open Reading Frame". They have been shown to regulate gene expression by novel mechanisms such as RNA interference, gene co-suppression, gene silencing, imprinting and DNA demethylation. It is becoming clear that these novel RNAs perform critical functions during development and cell differentiation. There is also mounting evidence of their involvement in cancer and neurological diseases. Together, all this information indicates that ncRNAs are emerging as a new class of functional transcripts in eukaryotes. Therefore, great challenges lie in the years ahead: understanding the molecular biology of higher organisms will require revealing all proteins (Proteome), all ncRNAs (RNome) and their interactions (Interactome) in the complex molecular scenario within eukaryotic cells.

Animals↗

PubMed2006

cDNA cloning, gene organization and variant specific expression of HIF-1 alpha in high altitude yak (Bos grunniens).

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factor consisting of HIF-1alpha and HIF-1beta subunits. HIF-1alpha is the oxygen-regulated subunit of HIF-1, which regulates the transcription of genes involved in oxygen homeostasis in response to hypoxia. Yak (Bos grunniens), a mammal native to high altitude (HA) region ( approximately 3500-5500 m), has successfully adapted over many generations to the chronic hypoxia of HA. In the present work, cDNA encoding HIF-1alpha has been cloned from the blood of yak. Tissue specific expression of the mRNA was analyzed in blood, heart, lung, liver and kidney by RT-PCR with primers from three different regions of cDNA. The HIF-1alpha expression was liver and blood specific. The HIF-1alpha mRNA contains 823 bp long 3'UTR that is AU-rich and contains ten AUUUA pentamers and two overlapping copies of the nonamer UUAUUUAUUUAUU. Three potential microRNAs, hsa-miR-107/mmu-miR-107/rno-miR-107, hsa-miR-18b and hsa-miR-135a/mmu-miR-135a/rno-miR-135a, targeting 3'UTR of yak HIF-1alpha, were identified by using target prediction software. The CDS encodes for 823 residues of amino acids and showed 99%, 95%, 92%, 90% and 90% similarity to domestic cattle, human, plateau pika, mouse and rat HIF-1alpha, respectively. HIF-1alpha cDNA, cloned and sequenced in the present work has revealed the evolutionary conservation through multiple sequence alignment. Liver and blood specific stability of HIF-1alpha mRNA appears miR-107 regulated.

Altitude↗

PubMed2006

Non-coding RNAs: lost in translation?

In the last ten years, several RNAs with no protein-coding potential have been accumulating in RNA databases and are in need of further molecular characterization. At the same time, examples of non-coding RNAs (ncRNAs) such as microRNAs, small RNAs, small interfering RNAs (siRNAs) and medium/large RNAs with various functions have been described in the literature. Recent evidence points to a widespread role of these molecules in eukaryotic cells, suggesting that the majority of the new ncRNA examples might have specific functions. The aim of this review is to describe several new functional ncRNAs that have been recently identified and characterized, providing some clues that these molecules might not be produced by chance or as by-products of transcription as has been speculated.

Animals↗

PubMed2025

KDM3B Regulates Postradiation Fibrotic Responses in Prostate Stroma via N6-methyladenosine Modification of LOX.

PURPOSE: Genome-wide association studies have uncovered single-nucleotide polymorphisms (SNPs) linked to radiation therapy (RT)-induced toxicities in patients with prostate cancer. SNP rs17599026, located in intron 21 of the KDM3B gene, has been associated with late-onset urinary toxicity, with an increased frequency of urination observed 2 years post-RT compared with pretreatment conditions. This study aimed to explore the underlying mechanisms driving this association. METHODS AND MATERIALS: A clustered regularly interspaced short palindromic repeats-dead Cas9 prime editing system was used to mimic KDM3B genetic variants in prostate stromal cell lines. Murine models with wild-type and heterozygous Kdm3b genotypes were used to assess fibrosis following radiation. RNA immunoprecipitation, transcript stability assays, and protein analysis elucidated the role of N6-methyladenosine (m6A) modification in regulating lysyl oxidase (LOX) expression. α-ketoglutarate (α-KG) supplementation was tested for its effects on KDM3B protein stability, LOX expression, and fibrosis mitigation. RESULTS: The rs17599026 SNP reduced KDM3B protein expression via circular RNA and microRNA-mediated mechanisms, leading to decreased m6A modification and increased stability of LOX messenger RNA. Elevated LOX expression promoted collagen cross-linking and fibrosis in prostate stroma. α-KG supplementation restored KDM3B protein levels, reduced LOX expression, and mitigated fibrosis in vitro and in vivo. CONCLUSIONS: KDM3B genetic variations influence radiation-induced fibrosis through posttranscriptional regulation of LOX. Dietary α-KG supplementation may serve as a mechanism-based strategy to alleviate radiation toxicity in patients with prostate cancer, offering a potential therapeutic pathway to improve treatment outcomes.

Male↗

PubMed2005

The dialectics of cancer: A theory of the initiation and development of cancer through errors in RNAi.

The recent discoveries of the RNA-mediated interference system in cells could explain all of the known features of human carcinogenesis. A key, novel idea, proposed here, is that the cell has the ability to recognise a mutated protein and/or mRNA. Secondly, the cell can generate its own short interfering RNA (siRNA) using an RNA polymerase to destroy mutated mRNA, even when only a single base pair in the gene has mutated. The anti-sense strand of the short RNA molecule (called sicRNA), targets the mutated mRNA of an oncogene or a tumour suppressor. The resulting double stranded RNA, using the RNA-induced silencing complex in the cytoplasm dices the mutated mRNA. In cancer-prone tissues, during cell mitosis, the sicRNA complex can move into the nucleus to target the mutated gene. The sicRNA, possibly edited by dsRNA-specific adenosine deaminase, converting adenosines to inosines, can be retained in the nucleus, with enhanced destructive capability. The sicRNA triggers the assembly of protein complexes leading to epigenetic modification of the promoter site of the mutant gene, specifically methylation of cytosines. In some instances, instead of methylation, the homologous DNA is degraded, leading to loss of heterozygosity. The factors controlling these two actions are unknown but the result is gene silencing or physical destruction of the mutant gene. The cell survives dependent on the functioning of the single, wild-type allele. An error in RNAi defence occurs when the sicRNA enters the nucleus and targets the sense strand of the wrong DNA. The sicRNA, because of the similarity of its short sequence and relaxed stringency, can target other RNAs, which are being transcribed. This can result in the methylation of the wrong promoter site of a gene or LOH of that region. In the vast majority of these cases, the aberrant hybridisations will have no effect on cell function or apoptosis eliminates non-viable cells. On a rare occasion, a preneoplastic cell is initiated when aberrant hybridisations switches on/off a gene involved in apoptosis, as well as a gene involved in cell proliferation and DNA damage surveillance. Genetic instability results when the sicRNA competes for a repeat sequence in the centromere or telomere, leading to gross chromosomal rearrangements. A malignancy develops when the sicRNAs fortuitously targets a microRNA (miRNA) or activates a transcription factor, resulting in the translation of a large number of new genes, alien to that tissue. This leads to dedifferentiation of the tissue, a resculpting of the histone code, chromosomal rearrangements, along a number of specific pathways, the gain of immortality and the dissemination of a metastatic cancer.

CpG Islands↗

PubMed2005

A screen for conserved sequences with biased base composition identifies noncoding RNAs in the A-T rich genome of Plasmodium falciparum.

Noncoding RNAs (ncRNAs) such as snRNAs, snoRNAs and microRNAs play important roles in transcription and translation control. These ncRNAs have yet to be discovered in the malarial parasite Plasmodium falciparum, an organism in which these basic biological processes are poorly understood. Inspired by a report by Klein et al., we initiated a bioinformatics screen to uncover several candidate ncRNAs from the parasite genome using two simple criteria: first, elevated GC content in the highly A-T rich intergenic regions of the P. falciparum genome and second, conservation of sequence homology between malaria parasite species. We show that all the annotated tRNAs can be successfully identified in our screen as well as several new candidates that show homology to snRNAs and snoRNAs, and ten candidate ncRNAs of unknown function. Three of the candidate snRNAs, a predicted selenocysteine tRNA and two candidates of unknown function are expressed in asexual stage parasites, further validating the screen. With these results, the biological processes underlying RNA-mediated regulation of transcription, translation and splicing can be studied in an important human pathogen.

Animals↗

PubMed2004

The C. elegans Polycomb gene SOP-2 encodes an RNA binding protein.

Epigenetic silencing of Hox cluster genes by Polycomb group (PcG) proteins is thought to involve the formation of a stably inherited repressive chromatin structure. Here we show that the C. elegans-specific PcG protein SOP-2 directly binds to RNA through three nonoverlapping regions, each of which is essential for its localization to characteristic nuclear bodies and for its in vivo function in the repression of Hox genes. Functional studies indicate that the RNA involved in SOP-2 binding is distinct from either siRNA or microRNA. Remarkably, the vertebrate PcG protein Rae28, which is functionally and structurally related to SOP-2, also binds to RNA through an FCS finger domain. Substitution of the Rae28 FCS finger for the essential RNA binding region of SOP-2 partially restores localization to nuclear bodies. These observations suggest that direct binding to RNA is an evolutionarily conserved and potentially important property of PcG proteins.

Animals↗

PubMed2026

Genomic and epigenetic regulatory mechanisms in exercise-based rehabilitation processes: Cellular and tissue remodeling, microvascular adaptation, and circulating biomarkers.

While exercise-based rehabilitation is known to positively impact functionally related parameters, the role of genomic and epigenomic responses coordinated with cellular, extracellular matrix (ECM), mitochondrial, and microvascular adaptations remains insufficiently investigated. This narrative review summarizes mechanistic evidence linking exercise-associated mechanical, metabolic, hypoxia-redox, inflammatory, and hemodynamic stimuli with tissue remodeling and clinically relevant biomarkers. Current findings indicate that integrin-focal adhesion kinase (FAK) signaling and Hippo YAP/TAZ pathways contribute to mechanical signal transduction, cytoskeletal regulation, and gene expression, whereas metabolic adaptation, ATP homeostasis, and protein synthesis are regulated through AMPK-PGC-1α, SIRT1, and mTOR-dependent pathways. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA regulation, further influence cell-specific responses in myofibers, satellite cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and immune cells. In addition, VEGF-VEGFR2, eNOS-NO, and KLF2/KLF4 signaling, together with extracellular matrix turnover and inflammation resolution, contribute to tissue repair and microvascular adaptation during rehabilitation. Importantly, acute exercise-induced molecular responses should not be interpreted as direct evidence of sustained tissue adaptation. Circulating microRNAs, extracellular vesicles, cell-free DNA, collagen-related markers, and vascular proteins represent promising approaches for monitoring rehabilitation-related changes; however, their clinical translation remains limited by challenges related to tissue specificity, biomarker kinetics, analytical variability, and the need for standardized validation alongside structural and functional outcomes.

AMPK–PGC-1α signaling↗

PubMed2006

Neuronal RNA granules: movers and makers.

RNA localization contributes to cell polarity and synaptic plasticity. Evidence will be discussed that RNA transport and local translation in neurons may be more intimately linked than originally thought. Second, neuronal RNA granules, originally defined as intermediates involved in mRNA transport, are much more diverse in their composition and functions than previously anticipated. We focus on three classes of RNA granules that include transport RNPs, stress granules, and P bodies and discuss their potential functions in RNA localization, microRNA-mediated translational regulation, and mRNA degradation.

Animals↗

PubMed2005

Stem cell regulation in the Arabidopsis shoot apical meristem.

The aerial structure of higher plants is generated dynamically throughout the life cycle through the activity of stem cells that are located at the growing shoot tip, the apical meristem. The stem cells continuously divide to renew themselves and provide cells for leaf, stem and flower formation. Stem cell maintenance is governed by intercellular communication between the apical stem cells and the underlying organizing centre. Recent advances have been made in understanding the mechanisms that induce shoot stem cell identity, and that control the position and size of the organizing centre. Elements such as chromatin remodeling factors, transcription factors and microRNAs are newly implicated in these regulatory processes. These advances provide a framework for our understanding of how signals are integrated to specify and position the stem cell niche in the shoot apical meristem.

Arabidopsis↗

PubMed2005

Root development--branching into novel spheres.

Recent progress in deciphering the genetics of Arabidopsis root development has been driven by the availability of novel molecular tools. For instance, combining enhancer trap lines and microarray analyses enabled the creation of an expression map for over 22000 genes at cellular resolution. Such expression profiles often suggest redundant action of homologous genes, which has indeed been observed for several pivotal factors that are required for the organization and maintenance of root meristems. Additional regulators of root development are also being identified by analysis of natural genetic variation. Moreover, microRNA control of gene expression has recently been implicated in root development, and progress has been made in understanding the interplay between environmental and genetic factors in root branching.

Arabidopsis↗

PubMed2026

Establishment of a cBSA-mediated miRNA delivery system in Camellia sinensis and functional validation of the Cs-miR163/CsSK1 module in cold stress response.

Cold stress severely limits tea (Camellia sinensis) yield and quality. MicroRNAs (miRNAs) are key post-transcriptional regulators of plant cold responses; however, in vivo functional validation in tea plants is hindered by the lack of efficient genetic transformation and nucleic acid delivery systems. In this study, a cationized bovine serum albumin (cBSA)-mediated miRNA delivery system was established in tea plants. The cold-responsive miRNA Cs-miR163 and its target gene CsSK1 (a negative regulator of cold tolerance) were used as a model. Direct cleavage of CsSK1 mRNA by Cs-miR163 was confirmed by 5' RLM-RACE and GUS transient expression assays, and enhanced cold tolerance was demonstrated in Arabidopsis overexpression lines. The cBSA preparation protocol was optimized, yielding stable cBSA/miRNA complexes with high protective capacity across temperatures of 15-35 °C and pH 4.5-7.2. Delivery parameters were systematically evaluated; optimal conditions were determined as 2 mg/mL cBSA with 10 nM miRNA and solution uptake into 3-cm cuttings for 5 days, enhancing miRNA delivery efficiency by approximately 48-fold. Transmission electron microscopy provided direct ultrastructural evidence that cBSA/miRNA nanocomplexes are internalized into tea plant cells via adsorptive-mediated endocytosis involving electrostatic membrane adsorption, membrane invagination, and cytoplasmic release. Under optimized conditions, cBSA-mediated delivery of Cs-miR163 silenced CsSK1 expression by approximately 72%, reduced relative electrolyte leakage and ROS accumulation, and markedly enhanced cold tolerance. The regulatory role of the Cs-miR163/CsSK1 module was clarified, and the established system provides a promising strategy for functional genomics in woody plants that warrants further testing in additional species and tissues.

Camellia sinensis↗