We recently proposed that competitive endogenous RNAs (ceRNAs) sequester microRNAs to regulate mRNA transcripts containing common microRNA recognition elements (MREs). However, the functional role of ...ceRNAs in cancer remains unknown. Loss of PTEN, a tumor suppressor regulated by ceRNA activity, frequently occurs in melanoma. Here, we report the discovery of significant enrichment of putative PTEN ceRNAs among genes whose loss accelerates tumorigenesis following Sleeping Beauty insertional mutagenesis in a mouse model of melanoma. We validated several putative PTEN ceRNAs and further characterized one, the ZEB2 transcript. We show that ZEB2 modulates PTEN protein levels in a microRNA-dependent, protein coding-independent manner. Attenuation of ZEB2 expression activates the PI3K/AKT pathway, enhances cell transformation, and commonly occurs in human melanomas and other cancers expressing low PTEN levels. Our study genetically identifies multiple putative microRNA decoys for PTEN, validates ZEB2 mRNA as a bona fide PTEN ceRNA, and demonstrates that abrogated ZEB2 expression cooperates with BRAFV600E to promote melanomagenesis.
Display omitted
► A Sleeping Beauty screen followed by MuTaME analysis discovered putative PTEN ceRNAs ► The PTEN ceRNA ZEB2 regulates PTEN in a miRNA-dependent manner ► ZEB2 loss activates PI3K/AKT signaling and promotes cell transformation ► Attenuated ZEB2 expression is found in melanoma and other human cancers
A transposon-based mutagenesis screen uncovers a striking enrichment of putative PTEN ceRNAs among mutated genes that accelerate tumorigenesis in a mouse model of melanoma. One candidate gene, ZEB2, regulates PI3K/AKT signaling and tumor-suppressive properties of PTEN.
Liver sinusoidal endothelial cells (LSECs) line the low shear, sinusoidal capillary channels of the liver and are the most abundant non-parenchymal hepatic cell population. LSECs do not simply form a ...barrier within the hepatic sinusoids but have vital physiological and immunological functions, including filtration, endocytosis, antigen presentation and leukocyte recruitment. Reflecting these multifunctional properties, LSECs display unique structural and phenotypic features that differentiate them from the capillary endothelium present within other organs. It is now clear that LSECs have a critical role in maintaining immune homeostasis within the liver and in mediating the immune response during acute and chronic liver injury. In this Review, we outline how LSECs influence the immune microenvironment within the liver and discuss their contribution to immune-mediated liver diseases and the complications of fibrosis and carcinogenesis.
Bacterial cell division is orchestrated by a tubulin homologue, FtsZ, which polymerizes to form a ring-like structure that is both a scaffold for the assembly of the bacterial cytokinetic machinery ...and, at least in part, a source of the energy for constriction. FtsZ assembly is tightly regulated, and a diverse repertoire of accessory proteins contributes to the formation of a functional division machine that is responsive to cell cycle status and environmental stress. In this Review, we describe the interaction of these proteins with FtsZ and discuss recent advances in our understanding of Z ring assembly.
Abstract Background For patients undergoing mitral valve (MV) repair, the indications for and results of concomitant tricuspid annuloplasty remain controversial. Objectives This study was designed to ...compare a strategy of routine concomitant tricuspid annuloplasty for moderate tricuspid regurgitation (TR) or tricuspid annular dilation in patients undergoing degenerative MV surgery. Methods Of 645 consecutive patients (mean age 57 ± 13 years) undergoing primary repair of degenerative mitral regurgitation between 2003 and 2011, 419 (65%) underwent concomitant tricuspid annuloplasty for moderate TR and/or tricuspid annular dilation. These patients were retrospectively analyzed with longitudinal echocardiographic follow-up. Results Patients undergoing tricuspid valve repair were older (mean age 59.2 years vs. 52.3 years), had worse right and left ventricular function and higher pulmonary artery pressures, and were more likely to have had atrial fibrillation than patients undergoing isolated MV repair (all p < 0.05). No significant difference in 30-day mortality, morbidity, or permanent pacemaker requirement was seen between treatment groups. Freedom from moderate TR at 7 years was not significantly different in the 2 groups, but multivariate analysis showed that tricuspid annuloplasty was independently associated with freedom from late moderate TR (p = 0.04), and was an independent predictor of recovery of right ventricular function (p = 0.02). Conclusions In patients with moderate TR or tricuspid annular dilation who were undergoing degenerative mitral repair, concomitant tricuspid annuloplasty is safe, effective, and associated with improved long-term right-sided remodeling. Routine treatment of moderate TR or tricuspid annular dilation at the time of MV repair appears to be beneficial.
Trends in peptide drug discovery Muttenthaler, Markus; King, Glenn F; Adams, David J ...
Nature reviews. Drug discovery,
04/2021, Letnik:
20, Številka:
4
Journal Article
Recenzirano
Since the introduction of insulin almost a century ago, more than 80 peptide drugs have reached the market for a wide range of diseases, including diabetes, cancer, osteoporosis, multiple sclerosis, ...HIV infection and chronic pain. In this Perspective, we summarize key trends in peptide drug discovery and development, covering the early efforts focused on human hormones, elegant medicinal chemistry and rational design strategies, peptide drugs derived from nature, and major breakthroughs in molecular biology and peptide chemistry that continue to advance the field. We emphasize lessons from earlier approaches that are still relevant today as well as emerging strategies such as integrated venomics and peptide-display libraries that create new avenues for peptide drug discovery. We also discuss the pharmaceutical landscape in which peptide drugs could be particularly valuable and analyse the challenges that need to be addressed for them to reach their full potential.
CRISPR-Cas9 technologies have transformed genome-editing of experimental organisms and have immense therapeutic potential. Despite significant advances in our understanding of the CRISPR-Cas9 system, ...concerns remain over the potential for off-target effects. Recent studies have addressed these concerns using whole-genome sequencing (WGS) of gene-edited embryos or animals to search for de novo mutations (DNMs), which may represent candidate changes introduced by poor editing fidelity. Critically, these studies used strain-matched, but not pedigree-matched controls and thus were unable to reliably distinguish generational or colony-related differences from true DNMs. Here we used a trio design and whole genome sequenced 8 parents and 19 embryos, where 10 of the embryos were mutagenised with well-characterised gRNAs targeting the coat colour Tyrosinase (Tyr) locus. Detailed analyses of these whole genome data allowed us to conclude that if CRISPR mutagenesis were causing SNV or indel off-target mutations in treated embryos, then the number of these mutations is not statistically distinguishable from the background rate of DNMs occurring due to other processes.
The Receptor for Activated C Kinase 1 (RACK1) is a member of the tryptophan-aspartate repeat (WD-repeat) family of proteins and shares significant homology to the β subunit of G-proteins (Gβ). RACK1 ...adopts a seven-bladed β-propeller structure which facilitates protein binding. RACK1 has a significant role to play in shuttling proteins around the cell, anchoring proteins at particular locations and in stabilising protein activity. It interacts with the ribosomal machinery, with several cell surface receptors and with proteins in the nucleus. As a result, RACK1 is a key mediator of various pathways and contributes to numerous aspects of cellular function. Here, we discuss RACK1 gene and structure and its role in specific signaling pathways, and address how posttranslational modifications facilitate subcellular location and translocation of RACK1. This review condenses several recent studies suggesting a role for RACK1 in physiological processes such as development, cell migration, central nervous system (CN) function and circadian rhythm as well as reviewing the role of RACK1 in disease.
Horizontal gene transfer can trigger rapid shifts in bacterial evolution. Driven by a variety of mobile genetic elements-in particular bacteriophages and plasmids-the ability to share genes within ...and across species underpins the exceptional adaptability of bacteria. Nevertheless, invasive mobile genetic elements can also present grave risks to the host; bacteria have therefore evolved a vast array of defences against these elements
. Here we identify two plasmid defence systems conserved in the Vibrio cholerae El Tor strains responsible for the ongoing seventh cholera pandemic
. These systems, termed DdmABC and DdmDE, are encoded on two major pathogenicity islands that are a hallmark of current pandemic strains. We show that the modules cooperate to rapidly eliminate small multicopy plasmids by degradation. Moreover, the DdmABC system is widespread and can defend against bacteriophage infection by triggering cell suicide (abortive infection, or Abi). Notably, we go on to show that, through an Abi-like mechanism, DdmABC increases the burden of large low-copy-number conjugative plasmids, including a broad-host IncC multidrug resistance plasmid, which creates a fitness disadvantage that counterselects against plasmid-carrying cells. Our results answer the long-standing question of why plasmids, although abundant in environmental strains, are rare in pandemic strains; have implications for understanding the dissemination of antibiotic resistance plasmids; and provide insights into how the interplay between two defence systems has shaped the evolution of the most successful lineage of pandemic V. cholerae.
PDF
