Showing papers in "Cold Spring Harbor Perspectives in Medicine in 2016"
TL;DR: The role of HDACs in cancer and the therapeutic potential ofHDAC inhibitors (HDACi) as emerging drugs in cancer treatment are discussed.
Abstract: Over the last several decades, it has become clear that epigenetic abnormalities may be one of the hallmarks of cancer. Posttranslational modifications of histones, for example, may play a crucial role in cancer development and progression by modulating gene transcription, chromatin remodeling, and nuclear architecture. Histone acetylation, a well-studied posttranslational histone modification, is controlled by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). By removing acetyl groups, HDACs reverse chromatin acetylation and alter transcription of oncogenes and tumor suppressor genes. In addition, HDACs deacetylate numerous nonhistone cellular substrates that govern a wide array of biological processes including cancer initiation and progression. This review will discuss the role of HDACs in cancer and the therapeutic potential of HDAC inhibitors (HDACi) as emerging drugs in cancer treatment.
724 citations
TL;DR: This review focuses on the cell-cycle arrest and apoptosis functions of p53, their roles in tumor suppression, and the regulation of cell fate decision after p53 activation.
Abstract: P53 is a transcription factor highly inducible by many stress signals such as DNA damage, oncogene activation, and nutrient deprivation. Cell-cycle arrest and apoptosis are the most prominent outcomes of p53 activation. Many studies showed that p53 cell-cycle and apoptosis functions are important for preventing tumor development. p53 also regulates many cellular processes including metabolism, antioxidant response, and DNA repair. Emerging evidence suggests that these noncanonical p53 activities may also have potent antitumor effects within certain context. This review focuses on the cell-cycle arrest and apoptosis functions of p53, their roles in tumor suppression, and the regulation of cell fate decision after p53 activation.
692 citations
TL;DR: This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.
Abstract: β-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related β-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of β-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to β-lactams is primarily because of bacterially produced β-lactamase enzymes that hydrolyze the β-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum β-lactamase inhibitors that work against many problematic β-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of β-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.
560 citations
TL;DR: Aminoglycosides found widespread use as first-line agents in the early days of antimicrobial chemotherapy, but were eventually replaced in the 1980s with cephalosporins, carbapenems, and fluoroquinolones.
Abstract: Aminoglycosides are natural or semisynthetic antibiotics derived from actinomycetes. They were among the first antibiotics to be introduced for routine clinical use and several examples have been approved for use in humans. They found widespread use as first-line agents in the early days of antimicrobial chemotherapy, but were eventually replaced in the 1980s with cephalosporins, carbapenems, and fluoroquinolones. Aminoglycosides synergize with a variety of other antibacterial classes, which, in combination with the continued increase in the rise of multidrug-resistant bacteria and the potential to improve the safety and efficacy of the class through optimized dosing regimens, has led to a renewed interest in these broad-spectrum and rapidly bactericidal antibacterials.
530 citations
TL;DR: It appears as if p53 is multitasking in providing protection from cancer development by maintaining genome stability by overseeing the activity of various DNA-repair systems.
Abstract: The cells in the human body are continuously challenged by a variety of genotoxic attacks. Erroneous repair of the DNA can lead to mutations and chromosomal aberrations that can alter the functions of tumor suppressor genes or oncogenes, thus causing cancer development. As a central tumor suppressor, p53 guards the genome by orchestrating a variety of DNA-damage-response (DDR) mechanisms. Already early in metazoan evolution, p53 started controlling the apoptotic demise of genomically compromised cells. p53 plays a prominent role as a facilitator of DNA repair by halting the cell cycle to allow time for the repair machineries to restore genome stability. In addition, p53 took on diverse roles to also directly impact the activity of various DNA-repair systems. It thus appears as if p53 is multitasking in providing protection from cancer development by maintaining genome stability.
472 citations
TL;DR: The full potential of the tetracyclines class can be explored for use against current and emerging multidrug-resistant (MDR) pathogens, including carbapenem-resistant Enterobacteriaceae, MDR Acinetobacter species, and Pseudomonas aeruginosa.
Abstract: Tetracyclines possess many properties considered ideal for antibiotic drugs, including activity against Gram-positive and -negative pathogens, proven clinical safety, acceptable tolerability, and the availability of intravenous (IV) and oral formulations for most members of the class. As with all antibiotic classes, the antimicrobial activities of tetracyclines are subject to both class-specific and intrinsic antibiotic-resistance mechanisms. Since the discovery of the first tetracyclines more than 60 years ago, ongoing optimization of the core scaffold has produced tetracyclines in clinical use and development that are capable of thwarting many of these resistance mechanisms. New chemistry approaches have enabled the creation of synthetic derivatives with improved in vitro potency and in vivo efficacy, ensuring that the full potential of the class can be explored for use against current and emerging multidrug-resistant (MDR) pathogens, including carbapenem-resistant Enterobacteriaceae, MDR Acinetobacter species, and Pseudomonas aeruginosa.
347 citations
TL;DR: Several roles of BAF and PBAF complexes in cancer are reviewed, including transcriptional regulation, DNA repair, and regulation of chromatin architecture and topology, and more recent results highlight the need for new techniques to study these complexes.
Abstract: During the last decade, a host of epigenetic mechanisms were found to contribute to cancer and other human diseases. Several genomic studies have revealed that ∼20% of malignancies have alterations of the subunits of polymorphic BRG-/BRM-associated factor (BAF) and Polybromo-associated BAF (PBAF) complexes, making them among the most frequently mutated complexes in cancer. Recurrent mutations arise in genes encoding several BAF/PBAF subunits, including ARID1A, ARID2, PBRM1, SMARCA4, and SMARCB1 These subunits share some degree of conservation with subunits from related adenosine triphosphate (ATP)-dependent chromatin remodeling complexes in model organisms, in which a large body of work provides insight into their roles in cancer. Here, we review the roles of BAF- and PBAF-like complexes in these organisms, and relate these findings to recent discoveries in cancer epigenomics. We review several roles of BAF and PBAF complexes in cancer, including transcriptional regulation, DNA repair, and regulation of chromatin architecture and topology. More recent results highlight the need for new techniques to study these complexes.
292 citations
TL;DR: Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes and resistance genes acquired on plasmids confer low-level resistance that promotes the selection of mutational high- level resistance.
Abstract: Quinolone antimicrobials are widely used in clinical medicine and are the only current class of agents that directly inhibit bacterial DNA synthesis. Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA-enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity. Resistance has emerged with clinical use of these agents and is common in some bacterial pathogens. Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes are commonly in a localized domain of the GyrA and ParC subunits of gyrase and topoisomerase IV, respectively, and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include other antimicrobials as well as quinolones. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is because of Qnr proteins that protect the target enzymes from quinolone action, a mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones.
266 citations
TL;DR: Previously suggested to primarily attack the membranes of Gram-negative bacteria and to not easily select for resistant mutants, recent research exploring resistance and mechanisms of action has provided new perspectives.
Abstract: Antibiotic resistance among pathogenic bacteria is an ever-increasing issue worldwide. Unfortunately, very little has been achieved in the pharmaceutical industry to combat this problem. This has led researchers and the medical field to revisit past drugs that were deemed too toxic for clinical use. In particular, the cyclic cationic peptides polymyxin B and colistin, which are specific for Gram-negative bacteria, have been used as "last resort" antimicrobials. Before the 1980s, these drugs were known for their renal and neural toxicities; however, new clinical practices and possibly improved manufacturing have made them safer to use. Previously suggested to primarily attack the membranes of Gram-negative bacteria and to not easily select for resistant mutants, recent research exploring resistance and mechanisms of action has provided new perspectives. This review focuses primarily on the proposed alternative mechanisms of action, known resistance mechanisms, and how these support the alternative mechanisms of action.
253 citations
[...]
TL;DR: Uncovering the underlying mechanisms of the autophagy-p53 reciprocal functional interaction and has important implications for human disease and treatment.
Abstract: Macroautophagy (autophagy hereafter) captures, degrades, and recycles intracellular components to maintain metabolic homeostasis and protein and organelle quality control. Autophagy thereby promotes survival in starvation and prevents tissue degeneration. There is an important relationship between autophagy and p53. Autophagy suppresses p53 and also p53 activates autophagy. The suppression of p53 by autophagy is important for tumor promotion and likely also for preventing tissue degeneration. Alternatively, the activation of autophagy by p53 suggests that autophagy is part of the protective function of p53. Uncovering the underlying mechanisms of the autophagy-p53 reciprocal functional interaction and has important implications for human disease and treatment.
231 citations
TL;DR: The ketogenic diet leads to increases in circulating ketones, which may contribute to the efficacy in treating pharmacoresistant seizures, and is one treatment option for drug-resistant patients.
Abstract: Antiseizure drugs (ASDs), also termed antiepileptic drugs, are the main form of symptomatic treatment for people with epilepsy, but not all patients become free of seizures. The ketogenic diet is one treatment option for drug-resistant patients. Both types of therapy exert their clinical effects through interactions with one or more of a diverse set of molecular targets in the brain. ASDs act by modulation of voltage-gated ion channels, including sodium, calcium, and potassium channels; by enhancement of γ-aminobutyric acid (GABA)-mediated inhibition through effects on GABAA receptors, the GABA transporter 1 (GAT1) GABA uptake transporter, or GABA transaminase; through interactions with elements of the synaptic release machinery, including synaptic vesicle 2A (SV2A) and α2δ; or by blockade of ionotropic glutamate receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. The ketogenic diet leads to increases in circulating ketones, which may contribute to the efficacy in treating pharmacoresistant seizures. Production in the brain of inhibitory mediators, such as adenosine, or ion channel modulators, such as polyunsaturated fatty acids, may also play a role. Metabolic effects, including diversion from glycolysis, are a further postulated mechanism. For some ASDs and the ketogenic diet, effects on multiple targets may contribute to activity. Better understanding of the ketogenic diet will inform the development of improved drug therapies to treat refractory seizures.
TL;DR: This work discusses spatial heterogeneity as a fundamental biological feature of the microenvironment, which has been largely ignored, and highlights statistical approaches for addressing the emerging challenges based on these new approaches.
Abstract: Recent developments in studies of tumor heterogeneity have provoked new thoughts on cancer management. There is a desperate need to understand influence of the tumor microenvironment on cancer development and evolution. Applying principles and quantitative methods from ecology can suggest novel solutions to fulfil this need. We discuss spatial heterogeneity as a fundamental biological feature of the microenvironment, which has been largely ignored. Histological samples can provide spatial context of diverse cell types coexisting within the microenvironment. Advanced computer-vision techniques have been developed for spatial mapping of cells in histological samples. This has enabled the applications of experimental and analytical tools from ecology to cancer research, generating system-level knowledge of microenvironmental spatial heterogeneity. We focus on studies of immune infiltrate and tumor resource distribution, and highlight statistical approaches for addressing the emerging challenges based on these new approaches.
TL;DR: The history and current standing of efforts to understand the specific mechanisms by which TP53 acts as a tumor suppressor are reviewed and how they complement each other in tumor suppression are reviewed.
Abstract: The fundamental biological importance of the Tp53 gene family is highlighted by its evolutionary conservation for more than one billion years dating back to the earliest multicellular organisms. The TP53 protein provides essential functions in the cellular response to diverse stresses and safeguards maintenance of genomic integrity, and this is manifest in its critical role in tumor suppression. The importance of Tp53 in tumor prevention is exemplified in human cancer where it is the most frequently detected genetic alteration. This is confirmed in animal models, in which a defective Tp53 gene leads inexorably to cancer development, whereas reinstatement of TP53 function results in regression of established tumors that had been initiated by loss of TP53. Remarkably, despite extensive investigation, the specific mechanisms by which TP53 acts as a tumor suppressor are yet to be fully defined. We review the history and current standing of efforts to understand these mechanisms and how they complement each other in tumor suppression.
TL;DR: There is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities.
Abstract: This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.
TL;DR: Alteration of HOX gene expression causes both uterine developmental abnormalities and impaired adult endometrial development that prevent implantation and lead to female infertility.
Abstract: HOX genes convey positional identity that leads to the proper partitioning and adult identity of the female reproductive track. Abnormalities in reproductive tract development can be caused by HOX gene mutations or altered HOX gene expression. Diethylstilbestrol (DES) and other endocrine disruptors cause Mullerian defects by changing HOX gene expression. HOX genes are also essential regulators of adult endometrial development. Regulated HOXA10 and HOXA11 expression is necessary for endometrial receptivity; decreased HOXA10 or HOXA11 expression leads to decreased implantation rates. Alternation of HOXA10 and HOXA11 expression has been identified as a mechanism of the decreased implantation associated with endometriosis, polycystic ovarian syndrome, leiomyoma, polyps, adenomyosis, and hydrosalpinx. Alteration of HOX gene expression causes both uterine developmental abnormalities and impaired adult endometrial development that prevent implantation and lead to female infertility.
TL;DR: Some of the recent advances in developing and testing drugs targeting the PRC2 as well as emerging results from clinical trials using these drugs in the treatment of human cancers are discussed.
Abstract: The chromatin environment is modulated by a machinery of chromatin modifiers, required for the specification and maintenance of cell fate. Many mutations in the machinery have been linked to the development and progression of cancer. In this review, we give a brief introduction to Polycomb group (PcG) proteins, their assembly into Polycomb repressive complexes (PRCs) and the normal physiological roles of these complexes with a focus on the PRC2. We review the many findings of mutations in the PRC2 coding genes, both loss-of-function and gain-of-function, associated with human cancers and discuss potential molecular mechanisms involved in the contribution of PRC2 mutations to cancer development and progression. Finally, we discuss some of the recent advances in developing and testing drugs targeting the PRC2 as well as emerging results from clinical trials using these drugs in the treatment of human cancers.
TL;DR: The clinical significance of TP53 mutation is dependent on tumor subtype and context, and understanding the clinical impact of mutation will require integrating mutation-specific information (type, frequency, and predicted impact) with data on haplotypes and on loss of heterozygosity.
Abstract: Amid the complexity of genetic alterations in human cancer, TP53 mutation appears as an almost invariant component, representing by far the most frequent genetic alteration overall. Compared with previous targeted sequencing studies, recent integrated genomics studies offer a less biased view of TP53 mutation patterns, revealing that >20% of mutations occur outside the DNA-binding domain. Among the 12 mutations representing each at least 1% of all mutations, five occur at residues directly involved in specific DNA binding, four affect the tertiary fold of the DNA-binding domain, and three are nonsense mutations, two of them in the carboxyl terminus. Significant mutations also occur in introns, affecting alternative splicing events or generating rearrangements (e.g., in intron 1 in sporadic osteosarcoma). In aggressive cancers, mutation is so common that it may not have prognostic value (all these cancers have impaired p53 function caused by mutation or by other mechanisms). In several other cancers, however, mutation makes a clear difference for prognostication, as, for example, in HER2-enriched breast cancers and in lung adenocarcinoma with EGFR mutations. Thus, the clinical significance of TP53 mutation is dependent on tumor subtype and context. Understanding the clinical impact of mutation will require integrating mutation-specific information (type, frequency, and predicted impact) with data on haplotypes and on loss of heterozygosity.
TL;DR: The availability of large-scale genomic profiling datasets, like those from The Cancer Genome Atlas Research Network, have provided the opportunity to evaluate the consequences of MDM2 amplification and SNP inheritance across high-quality tumor samples from diverse cancer indications.
Abstract: Mouse double minute 2 (MDM2) is a critical negative regulator of the tumor suppressor p53, playing a key role in controlling its transcriptional activity, protein stability, and nuclear localization. MDM2 expression is up-regulated in numerous cancers, resulting in a loss of p53-dependent activities, such as apoptosis and cell-cycle arrest. Genetic amplification and inheritance of MDM2 promoter single-nucleotide polymorphisms (SNPs) are the two best-studied mechanisms for up-regulating MDM2 activity. This article provides an overview of these events in human cancer, highlighting the frequent occurrence of MDM2 amplification in sarcoma and the role of SNP309 and SNP285 in regulating MDM2 expression and cancer risk. The availability of large-scale genomic profiling datasets, like those from The Cancer Genome Atlas Research Network, have provided the opportunity to evaluate the consequences of MDM2 amplification and SNP inheritance across high-quality tumor samples from diverse cancer indications.
TL;DR: This work will review the historical aspects of the development of DAP, as well as the current knowledge on its mechanism of action and pathways to resistance in a clinically relevant context, to review the clinical use of this antibiotic.
Abstract: Lipopeptides are natural product antibiotics that consist of a peptide core with a lipid tail with a diverse array of target organisms and mechanisms of action. Daptomycin (DAP) is an example of these compounds with specific activity against Gram-positive organisms. DAP has become increasingly important to combat infections caused by Gram-positive bacteria because of the presence of multidrug resistance in these organisms, particularly in methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). However, emergence of resistance to DAP during therapy is a well-described phenomenon that threatens the clinical use of this antibiotic, limiting further the therapeutic options against both MRSA and VRE. This work will review the historical aspects of the development of DAP, as well as the current knowledge on its mechanism of action and pathways to resistance in a clinically relevant context.
TL;DR: Two strategies to reengineer the tumor microenvironment-vessel normalization and decompression-that can alleviate hypoxia are summarized and discussed, and how these two strategies alone and in combination with each other-or other therapeutic strategies-may overcome the challenges posed by cancer heterogeneity are discussed.
Abstract: Solid tumors consist of cancer cells and stromal cells, including resident and transiting immune cells-all ensconced in an extracellular matrix (ECM)-nourished by blood vessels and drained by lymphatic vessels. The microenvironment constituents are abnormal and heterogeneous in morphology, phenotype, and physiology. Such irregularities include an inefficient tumor vascular network comprised of leaky and compressed vessels, which impair blood flow and oxygen delivery. Low oxygenation in certain tumor regions-or focal hypoxia-is a mediator of cancer progression, metastasis, immunosuppression, and treatment resistance. Thus, repairing an abnormal and heterogeneous microenvironment-and hypoxia in particular-can significantly improve treatments of solid tumors. Here, we summarize two strategies to reengineer the tumor microenvironment (TME)-vessel normalization and decompression-that can alleviate hypoxia. In addition, we discuss how these two strategies alone and in combination with each other-or other therapeutic strategies-may overcome the challenges posed by cancer heterogeneity.
TL;DR: Together with bioinformatic analyses on modern-day sequences, these studies predict an ancient origin of resistance that long precedes the use of antibiotics in the clinic, and is important in predicting its future evolution.
Abstract: Antibiotic resistance is a global problem that is reaching crisis levels The global collection of resistance genes in clinical and environmental samples is the antibiotic "resistome," and is subject to the selective pressure of human activity The origin of many modern resistance genes in pathogens is likely environmental bacteria, including antibiotic producing organisms that have existed for millennia Recent work has uncovered resistance in ancient permafrost, isolated caves, and in human specimens preserved for hundreds of years Together with bioinformatic analyses on modern-day sequences, these studies predict an ancient origin of resistance that long precedes the use of antibiotics in the clinic Understanding the history of antibiotic resistance is important in predicting its future evolution
TL;DR: Drug-inactivating mechanisms include phosphorylation of the 2'-hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases.
Abstract: Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome’s interaction with the antibiotic. Alternatively, mono- or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) + msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2′-hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences.
TL;DR: It is realized that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the coexpressed p53 isoforms and that unbalancing expression of different p 53 isoforms leads to cancer, premature aging, (neuro)degenerative diseases, inflammation, embryo malformations, or defects in tissue regeneration.
Abstract: It is poorly understood how a single protein, p53, can be responsive to so many stress signals and orchestrates very diverse cell responses to maintain/restore cell/tissue functions. The uncovering that TP53 gene physiologically expresses, in a tissue-dependent manner, several p53 splice variants (isoforms) provides an explanation to its pleiotropic biological activities. Here, we summarize a decade of research on p53 isoforms. The clinical studies and the diverse cellular and animal models of p53 isoforms (zebrafish, Drosophila, and mouse) lead us to realize that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the coexpressed p53 isoforms and that unbalancing expression of different p53 isoforms leads to cancer, premature aging, (neuro)degenerative diseases, inflammation, embryo malformations, or defects in tissue regeneration. Cracking the p53 isoforms' code is, thus, a necessary step to improve cancer treatment. It also opens new exciting perspectives in tissue regeneration.
TL;DR: The most recent evidence on the underlying roles of MLL3/MLL4 and UTX in cancer is reviewed and key outstanding questions are highlighted to help drive future research and contribute to the fundamental understanding of cancer and facilitate identification of therapeutic opportunities.
Abstract: During development, precise spatiotemporal patterns of gene expression are coordinately controlled by cis-regulatory modules known as enhancers. Their crucial role in development helped spur numerous studies aiming to elucidate the functional properties of enhancers within their physiological and disease contexts. In recent years, the role of enhancer malfunction in tissue-specific tumorigenesis is increasingly investigated. Here, we direct our focus to two primary players in enhancer regulation and their role in cancer pathogenesis: MLL3 and MLL4, members of the COMPASS family of histone H3 lysine 4 (H3K4) methyltransferases, and their complex-specific subunit UTX, a histone H3 lysine 27 (H3K27) demethylase. We review the most recent evidence on the underlying roles of MLL3/MLL4 and UTX in cancer and highlight key outstanding questions to help drive future research and contribute to our fundamental understanding of cancer and facilitate identification of therapeutic opportunities.
TL;DR: The normal regulation of the p53 pathway and the different mechanisms of pathway inhibition in cancer are reviewed, and these alterations in the context of the global genomic analyses that have been conducted across tumor types are discussed.
Abstract: The p53 pathway is perturbed in the majority of human cancers. Although this most frequently occurs through the direct mutation or deletion of p53 itself, there are a number of other alterations that can attenuate the pathway and contribute to tumorigenesis. For example, amplification of important negative regulators, MDM2 and MDM4, occurs in a number of cancers. In this work, we will review both the normal regulation of the p53 pathway and the different mechanisms of pathway inhibition in cancer, discuss these alterations in the context of the global genomic analyses that have been conducted across tumor types, and highlight the translational implications for cancer diagnosis and treatment.
TL;DR: The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies and its role as a potential geroprotector is discussed.
Abstract: Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector.
TL;DR: The ability of p53 to regulate metabolism is a powerful feature of p 53 biology that can both promote cell survival and act as a check on the inappropriate proliferation of cancer cells.
Abstract: The p53 protein is essential for the implementation of the cellular response to challenging environmental conditions. Reacting to stochastic nutrient stress, p53 integrates the activity of key metabolite-sensing pathways to coordinate an appropriate cell response. During starvation, p53 activity augments cell survival pathways, inhibits unnecessary growth, and promotes efficient nutrient generation, utilization, and conservation. Similarly, during oxygen stress, p53 facilitates redirection of cellular metabolism toward energy generation through nonoxidative means, the suppression of reactive oxygen species (ROS) generation, and ROS detoxification-promoting cell survival. However, if adverse conditions are too acute or persistent, p53 can switch roles to implement canonical cell killing. The ability of p53 to regulate metabolism is a powerful feature of p53 biology that can both promote cell survival and act as a check on the inappropriate proliferation of cancer cells.
TL;DR: This article will discuss the molecular biology underlying the effects of rapamycin and its physiological effects, evidence for Rapamycin as an antiaging compound, mechanisms by whichRapamycin may extend life span, and the potential limitations of rap Amycin as a antiaging molecule.
Abstract: Rapamycin is a Food and Drug Administration (FDA)-approved immunosuppressant and anticancer agent discovered in the soil of Easter Island in the early 1970s. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, which acts as a central integrator of nutrient signaling pathways. During the last decade, genetic and pharmaceutical inhibition of mTOR pathway signaling has been found to promote longevity in yeast, worms, flies, and mice. In this article, we will discuss the molecular biology underlying the effects of rapamycin and its physiological effects, evidence for rapamycin as an antiaging compound, mechanisms by which rapamycin may extend life span, and the potential limitations of rapamycin as an antiaging molecule. Finally, we will discuss possible strategies that may allow us to inhibit mTOR signaling safely while minimizing side effects, and reap the health, social, and economic benefits from slowing the aging process.
TL;DR: There is much evidence that HBx can contribute directly to HBV replication by acting on viral promoters embedded within protein coding sequences and indirectly by modulating cellular pathways to benefit virus replication.
Abstract: The efficient replication of hepatitis B virus (HBV) requires the HBV regulatory hepatitis B virus X (HBx) protein. The exact contributions of HBx are not fully understood, in part because of the limitations of the assays used for its study. When HBV replication is driven from a plasmid DNA, the contribution of HBx is modest. However, there is an absolute requirement for HBx in assays that recapitulate the infectious virus life cycle. There is much evidence that HBx can contribute directly to HBV replication by acting on viral promoters embedded within protein coding sequences. In addition, HBx may also contribute indirectly by modulating cellular pathways to benefit virus replication. Understanding the mechanism(s) of HBx action during virus replication may provide insight into novel ways to disrupt chronic HBV replication.
TL;DR: The evidence for epigenetic information carriers in mammalian sperm is reviewed, the emerging field of intergenerational transfer of environmental information is explored, and the role of mitochondria in epigenetic inheritance is explored.
Abstract: The inheritance of information beyond DNA sequence, known as epigenetic inheritance, has been implicated in a multitude of biological processes from control of plant flowering time to cancer in humans. In addition to epigenetic inheritance that occurs in dividing cells of a multicellular organism, it is also increasingly clear that at least some epigenetic information is transmitted via the gametes in a multitude of organisms, including mammals. Here, I review the evidence for epigenetic information carriers in mammalian sperm, and explore the emerging field of intergenerational transfer of environmental information.