Regulation of p14ARF Through Subnuclear Compartmentalization

The p53-mediated pathway cell cycle arrest and apoptosis is central to cancer and an important point of focus for therapeutics development. The p14ARF ("ARF") tumor suppressor induces the p53 pathway in response to oncogene activation or DNA damage. However, ARF is predominantly nucleolar in localization and engages in several interactions with nucleolar proteins, whereas p53 is nucleoplasmic. This raises the question as to how ARF initiates its involvement in the p53 pathway. We have found that UV irradiation of cells disrupts the interaction of ARF with two of its nucleolar binding partners, B23(NPM, nucleophosmin, NO38, numatrin) and topoisomerase I, and promotes an immediate and transient subnuclear redistribution of ARF to the nucleoplasm, where it can engage the p53 pathway (Lee et al, Cancer Research 65:9834-42; 2005). The results support a model in which the nucleolus serves as a p53 upstream sensor of cellular stress, and add to a growing body of evidence that nucleolar sequestration of ARF prevents activation of p53. The results also have therapeutic implications for therapies based on exploiting p53 and other cellular stress response pathways to suppress cancer.     

Causes and Consequences of Cysteine S-Glutathionylation

Post-translational S-glutathionylation occurs through the reversible addition of a proximal donor of glutathione to thiolate anions of cysteines in target proteins, where the modification alters molecular mass, charge, and structure/function and/or prevents degradation from sulfhydryl overoxidation or proteolysis. Catalysis of both the forward (glutathione S-transferase P) and reverse (glutaredoxin) reactions creates a functional cycle that can also regulate certain protein functional clusters, including those involved in redox-dependent cell signaling events. For translational application, S-glutathionylated serum proteins may be useful as biomarkers in individuals (who may also have polymorphic expression of glutathione S-transferase P) exposed to agents that cause oxidative or nitrosative stress.     

The Causes and Consequences of Color Vision

The ability to see colors is not universal in the animal kingdom. Those animals that can detect differences in the wavelengths of the electromagnetic spectrum glean valuable sensory information about their environment. They use color vision to forage, avoid predators, and find high-quality mates. In the past, the colors that humans could see clouded scientists’ study of animals’ color perception. Leaving that bias behind has led to new insights about how and why the color vision of animals evolved. This paper provides a brief introduction to color vision, the genetics of color vision in humans, what colors other animals see, and how scientists study color vision. We examine the consequences of having color vision, including speciation, loss of olfactory capabilities, and sexual selection.     

Causes and Consequences of the DNA Damage Response

A prerequisite for maintaining genome stability in all cell types is the accurate repair and efficient signaling of DNA double strand breaks (DSBs). It is believed that DSBs are initially detected by damage sensors that trigger the activation of transducing kinases. These transducers amplify the damage signal, which is then relayed to effector proteins, which regulate the progression of the cell cycle, DNA repair and apoptosis. Errors in the execution of the repair and/or signaling of DSBs can give rise to multi-systemic disorders characterized by tissue degeneration, infertility, immune system dysfunction, age-related pathologies and cancer. This special Spotlight issue of Cell Cycle highlights recent advances in our understanding of the biology and significance of the DNA damage response. A range of issues are addressed including mechanistic ones: what is the aberrant DNA structure that triggers the activation of the checkpoint - how does chromatin structure influence the recruitment of repair and checkpoint proteins- how does chromosomal instability contribute to the evolution of cancer. In addition, questions related to the physiology of the DNA damage response in normal and abnormal cells is explored: what is the in vivo consequence of altering specific amino acids in a DNA damage sensor- does DNA damage accumulation in stem cells cause aging- how is neurodegeneration linked to deficiencies in specific DNA repair pathways, and finally, what is the biological basis for selection of aberrant DNA damage responses in cancer cells?     

Carbonyl Stress in Bacteria: Causes and Consequences

Pathways of synthesis of the α-reactive carbonyl compound methylglyoxal (MG) in prokaryotes are described in this review. Accumulation of MG leads to development of carbonyl stress. Some pathways of MG formation are similar for both pro- and eukaryotes, but there are reactions specific for prokaryotes, e.g. the methylglyoxal synthase reaction. This reaction and the glyoxalase system constitute an alternative pathway of glucose catabolism–the MG shunt not associated with the synthesis of ATP. In violation of the regulation of metabolism, the cell uses MG shunt as well as other glycolysis shunting pathways and futile cycles enabling stabilization of its energetic status. MG was first examined as a biologically active metabolic factor participating in the formation of phenotypic polymorphism and hyperpersistent potential of bacterial populations. The study of carbonyl stress is interesting for evolutionary biology and can be useful for constructing highly effective producer strains.     

The PAL-Mechanism of Chromosome Maintenance: Causes and Consequences

It is generally accepted that cells with extensive, un-repaired DNA damage canescape cell cycle arrest only by disabling checkpoint pathways and they usuallyperish, after several divisions, presumably due to catastrophic events on theirchromosomes. Our recently discovered PAL-mechanism opens a new perspective,that some eukaryotic cells with short chromosome ends (telomeres), usually detectedas DNA damage, can escape permanent cell cycle arrest (senescence) under specialconditions, despite having intact checkpoints and even immortalize, despite lackingtelomerase or other telomere-elongation mechanisms. Here we present the firstevidence that telomerase-lacking, senescent cells generate DNA damage (singlestranded DNA) at internal chromosomal regions, while the telomere proximal singlestranded DNA appears to be either lost or repaired. This first evidence is from thebudding yeast model system. We also discuss the possible involvement of the PALmechanismin carcinogenesis.     

Causes and Consequences of Schadenfreude and Sympathy: A Developmental Analysis

Moral judgments and moral emotions are a ubiquitous feature of social interactions. Humans decide quickly and intuitively whether an action is morally right or wrong. Schadenfreude and sympathy, as emotional reactions to the misfortunes of others, are prototypical moral emotions. So far, however, little evidence exists concerning children’s understanding of schadenfreude. Within three studies, we investigated the experience of schadenfreude and sympathy among N = 364 children of different age groups. We interviewed the children while showing them picture stories. In the picture stories, we varied the behavior of the protagonist prior to a misfortune: (1) whether his behavior had been morally right or wrong, (2) whether the protagonist attained his goal, (3) whether the protagonist was responsible for the misfortune. In addition, in one study we varied (4) the emotional relationship of the interviewed children to the protagonist. Furthermore, we asked the children to decide whether they want to sit next to the protagonist or do him a favor. Results show that children experience sympathy as well as schadenfreude at the age of 4 years. Sympathy is more likely to arise when the protagonists of a story are likable, when these actors typically pursue morally positive goals, and if they are not responsible for their misfortune. In contrast, schadenfreude is more likely when the protagonist is disliked, when actors pursue immoral goals and if they are responsible for their misfortune. In addition, sympathy increases approach (helping behavior, sitting next to the agent and doing favors), whereas schadenfreude increases avoidance tendencies.     

Causes and Consequences of Genome Instability in Psychiatric and Neurodegenerative Diseases

Molecular Biology - Each neuron has 100–10000 connections (synapses) with other neural cells, therefore genome pathologies affecting a small proportion of brain cells are capable of causing...     

Harmful Cyanobacterial Blooms: Causes, Consequences, and Controls

Cyanobacteria are the Earth’s oldest oxygenic photoautotrophs and have had major impacts on shaping its biosphere. Their long evolutionary history (～3.5 by) has enabled them to adapt to geochemical and climatic changes, and more recently anthropogenic modifications of aquatic environments, including nutrient over-enrichment (eutrophication), water diversions, withdrawals, and salinization. Many cyanobacterial genera exhibit optimal growth rates and bloom potentials at relatively high water temperatures; hence global warming plays a key role in their expansion and persistence. Bloom-forming cyanobacterial taxa can be harmful from environmental, organismal, and human health perspectives by outcompeting beneficial phytoplankton, depleting oxygen upon bloom senescence, and producing a variety of toxic secondary metabolites (e.g., cyanotoxins). How environmental factors impact cyanotoxin production is the subject of ongoing research, but nutrient (N, P and trace metals) supply rates, light, temperature, oxidative stressors, interactions with other biota (bacteria, viruses and animal grazers), and most likely, the combined effects of these factors are all involved. Accordingly, strategies aimed at controlling and mitigating harmful blooms have focused on manipulating these dynamic factors. The applicability and feasibility of various controls and management approaches is discussed for natural waters and drinking water supplies. Strategies based on physical, chemical, and biological manipulations of specific factors show promise; however, a key underlying approach that should be considered in almost all instances is nutrient (both N and P) input reductions; which have been shown to effectively reduce cyanobacterial biomass, and therefore limit health risks and frequencies of hypoxic events.