File Name: nucleolus structure and function .zip
When cells are observed by phase contrast microscopy, nucleoli are among the most conspicuous structures. The nucleolus was formally described between and , but it was another century before it was discovered to be associated with a specific chromosomal locus, thus defining it as a cytogenetic entity. Nucleoli were first isolated in the s, from starfish oocytes.
- The Multiple Functions of the Nucleolus in Plant Development, Disease and Stress Responses
- The Cell Nucleus
- Cell nucleus
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The mechanical strength for the nucleus is provided by the nuclear matrix, a network of fibres and filaments which performs functions similar to the cytoskeleton. A nucleolus plural: nucleoli is the part of a eukaryotic cell where ribosomes are made. Breaks down food to produce energy in the form of ATP. PDF On computing the nucleolus of cooperative games.
The Multiple Functions of the Nucleolus in Plant Development, Disease and Stress Responses
Cell Stress, Vol. Abbreviations: Act. Conflict of interest statement: There is no conflict of interest. Nucleolar Stress: hallmarks, sensing mechanism and diseases. Cell Stress 2 6 : The nucleolus is a prominent subnuclear compartment, where ribosome biosynthesis takes place. Recently, the nucleolus has gained attention for its novel role in the regulation of cellular stress. Nucleolar stress is emerging as a new concept, which is characterized by diverse cellular insult-induced abnormalities in nucleolar structure and function, ultimately leading to activation of p53 or other stress signaling pathways and alterations in cell behavior.
Despite a number of comprehensive reviews on this concept, straightforward and clear-cut way criteria for a nucleolar stress state, regarding the factors that elicit this state, the morphological and functional alterations as well as the rationale for p53 activation are still missing. Based on literature of the past two decades, we herein summarize the evolution of the concept and provide hallmarks of nucleolar stress. Along with updated information and thorough discussion of existing confusions in the field, we pay particular attention to the current understanding of the sensing mechanisms, i.
In addition, we propose our own emphasis regarding the role of nucleolar protein NPM1 in the hallmarks of nucleolar stress and sensing mechanisms. Finally, the links of nucleolar stress to human diseases are briefly and selectively introduced.
However, during the past two decades, researchers have demonstrated that this is in fact an organelle having multiple complex functions. Numerous studies have listed triggers for nucleolar stress, characterized morphological and functional alterations, and dissected the molecules that induce activation of p53 signaling or other stress-responsive pathways.
While these studies enriched our understanding of the general features of nucleolar stress, many questions, especially those regarding the sensing mechanism, remain unanswered. In this review we summarize the literature describing the evolution of the concept, focusing on the hallmarks and the sensing mechanisms for nucleolar stress.
We will also discuss some key ambiguities in this field. Starting in the s, evidence has gradually accumulated that transcripts other than rRNAs can be produced and processed in the nucleolus .
In addition, the nucleolus was also found to functionally interact with Cajal bodies, other nuclear sub-compartments, to promote non-ribosomal RNA species maturation . This intriguingly showed that the nucleolus is involved in such diverse cellular events as signal recognition particle assembly, cell cycle regulation, DNA replication and repair, control of aging, response to viral infection, modulation of telomerase, and others  .
Overall, these clues indicate that the nucleolus is a multifunctional organelle. In parallel, many researchers noticed that some nucleolus-enriched proteins are frequently shuttled between the nucleolus and nucleoplasm. Remarkably, a number of nucleolar proteins translocate to the nucleoplasm in response to various stress conditions       .
This phenomenon was initially observed when ribosome biogenesis was blocked by Actinomycin D Act. D , a Pol I inhibitor  , and soon thereafter was also found in cells exposed to cytotoxic agents   , viral proteins  , ultraviolet radiation   , heat shock  and agents inducing DNA damage   , apoptosis or senescence   .
The links between the nucleolus and cellular stress were eventually proposed based on the findings that the nucleolus participates in regulating the abundance of the stress responsive protein p53       . In summary, the notion that the nucleolus plays a role in regulating cellular stress states represents at least two aspects of the same idea: p53 activation by nucleolar proteins.
One hypothesis emphasizes that the nucleolus is a sensor for cellular stresses, in which stress-induced nucleoplasmic translocation of nucleolar proteins, such as NPM1    and GLTSCR2  initiates p53 activation. ARF  among others in p53 interaction with its negative regulator MDM2, but placing less emphasis on their translocation. The term was originally referred to the stressful events that impair the homeostasis of ribosome biogenesis and activate the cellular stress response.
D  , or aberrant expression of nucleolar proteins  , which also impair ribosomal function. In general, nucleolar stress is now used to describe various stressor-induced impairments in nucleolar morphology and function that ultimately lead to disturbances in cell homeostasis through activation of p53 or other stress signaling Figure 1. Various stressors induce nucleolar stress, accompanied by morphological changes and functional defects, ultimately resulting in activation of p53 signaling pathway and altered cell behavior.
The idea that cell cycle progression may depend on some aspect of ribosome biogenesis was first implied in early studies on the cell cycle . In higher eukaryotes, Volarevic proved that deletion of RPS6 in the liver of adult mice abolished 40S ribosome biogenesis and inhibited cell proliferation following partial hepatectomy .
Identifying the correlation of interference of the nucleolar protein Bop1 and pdependent cell cycle arrest, Pestov et al. Indeed, this model of nucleolar stress, probably the first of its kind, is consistent with many observations under diverse pactivating stressors   .
The pioneering work conducted by Rubbi and Milner significantly solidified the notion of nucleolar stress . They aimed at resolving the puzzle of how signals in a large variety of cellular stress situations can be integrated by a single molecule, namely p A common phenomenon in all pinducing stresses is nucleolar disruption.
Based on a comparative meta-analysis of diverse stimuli that activate p53 signaling and induce nucleolar alteration, they hypothesized that the impairment of nucleolar function might stabilize p In fact, activation of p53 is induced by a wide range of cellular stresses, aside from the Pol I inhibitor Act.
D, which all cause disruption of nucleolar organization. The translocation of nucleophosmin NPM1, or B23 , an abundant nucleolar protein that is the most frequently reported to move to the nucleoplasm and cytoplasm upon various cellular insults was set as the criterion for nucleolus disruption. Rubbi and Milner demonstrated that NPM1 translocation, or nucleolus disruption following micropore UV irradiation over the nucleoli occurs prior to and independent of p53 induction.
Alternatively, p53 response can be induced by interfering with nucleolar function using an antibody against the nucleolar protein UBF upstream binding factor in the absence of any genotoxic insult.
Therefore, the model they proposed was the only one that could provide a unifying and coherent explanation for the action of all known pstabilizing agents. Following the principle of cellular events in response to stress conditions, we describe the following elements as the hallmarks of nucleolar stress.
Ribosom e biogenesis insults and a wide range of stimuli as stressors. Ribosome biogenesis comprises multiple steps accomplished in three distinct subnucleolar components, from Pol I transcription initiation to pre-rRNA processing and ribosomal assembly.
Any error that causes disturbance in ribosome biogenesis will lead to nucleolar stress. In fact, deletion or aberrant expression of a number of ribosomal proteins induce p53 stabilization and activation via disruption of ribosome biogenesis: Pestov et al.
Genetic inactivation of TIF-1A, a basal transcription initiation factor for Pol I, leads to nucleolar disruption, cell cycle arrest and pmediated apoptosis . Depletion of importin 7 IPO7 or exportin 1 XPO1 proteins impairs ribosome biogenesis and also initiates pdependent cell cycle arrest .
Microinjection of specific monoclonal antibodies against transcription factor UBF inhibits rRNA transcription and leads to p53 stabilization . Overall, systematic screening analysis revealed an extensive connection of p53 stabilization with nucleolar disruption induced by ribosomal protein depletion .
The chemotherapeutic agent Act. D is the mostly used nucleolar stress inducer. It may inhibit three individual RNA polymerases at different concentrations .
It is believed that Act. D can induce DNA damage and inhibit general transcription at high concentrations, such as nM, but selectively inhibits Pol I and induces ribosomal stress at low dose like 5 nM . Strikingly, as summarized by Rubbi and Milner, stressful conditions that can induce p53 activation can all induce nucleolar stress: these include UV light, hypoxia, heat shock, nucleotide depletion and various chemotherapeutic agents .
These stimuli were confirmed to simultaneously induce nucleolar stress and p53 activation by subsequent studies  . The rationale that stressors of diverse nature can all induce nucleolar stress has not been adequately discussed, thus has remained unknown for a long time.
Recently we found that common cellular insults that are able to induce p53 activation can also induce the translocation of NPM1, a hallmark of nucleolar stress, in a reactive oxygen species ROS -dependent manner. Moreover, our study added nutrient starvation and direct exposure to hydrogen peroxide H 2 O 2 to the growing list of nucleolar stress inducers .
In summary, the reported factors that induce nucleolar stress can be classified into two categories: canonical and non-canonical. The former points to those affecting homeostasis of ribosome biogenesis, whereas the latter includes a wide range of general cellular insults Figure 2. Two categories of nucleolar stress inducers are direct ribotoxic insults and a wide range of cellular insults. Unlike membrane-limited organelles, there is no structural barrier between the nucleolus and the surrounding nucleoplasm.
As a consequence, any soluble molecule can potentially traffic in and out of the nucleolus in a relatively free manner. Nucleolar stress causes a lot of nucleolar molecules to redistribute in the nucleus, or in other words, to be released from the nucleolus to the nucleoplasm.
This translocation or redistribution is thus considered as an indicator of nucleolar stress. NPM1 also known as B23, nucleophosmin, numatrin or NO38 is the most abundant protein in the nucleolus   and under diverse scenarios can dynamically shuttle both within nucleoli and between the nucleolus and the nucleoplasm or the cytoplasm   .
The known functions of this protein include the interaction with a plethora of macromolecules, for instance, Rb in the nucleus  and BAX in the cytoplasm  , and chaperoning activity protecting proteins from aggregation in the crowded nucleolar environment  . At exit of mitosis, NPM1, among other ribosomal processing proteins, undergoes bidirectional traffic between incipient nucleoli and perinucleolar bodies, which may contribute to nucleolar assembly in early G1 phase .
NPM1 is also responsible for the nuclear export of ribosomal protein L5 . Although the concept of nucleolar stress had not been proposed by then, the conditions under which they found NPM1 nucleoplasmic translocation belonged to general cellular stress or typical ribosomal stress.
With immunofluorescence technology, they first found that upon 48 hours serum-free medium starvation, NPM1 was diminished in nucleoli and appeared in the nucleoplasm, whereas refeeding of serum-containing medium relocated NPM1 protein to nucleolus  , indicating a reversible nucleoplasmic translocation capability of NPM1. They also noticed that ribosomal transcription inhibitors, such as Act.
D, were all able to induce NPM1 nucleoplasmic translocation . Even an iron chelator deferoxamine which showed anti-proliferation effects  , UV radiation  , viral infection  , hypoxia and oxidative stress H 2 O 2  all lead to nucleoplasmic translocation of NPM1.
Among the observations of nucleoplasmic translocation of NPM1, a great part described the association of this event with p53 signaling activation. Using the anti-cancer drug daunomycin, Chan et al. Then, Rubbi et al. Furthermore, Kurki et al.
Recently, we uncovered a redox mechanism of NPM1 for sensing nucleolar stress that causes p53 accumulation and activation . Therefore, as a most frequent event, NPM1 translocation should be regarded as a conspicuous hallmark of nucleolar stress.
The following nucleolar proteins exhibit nucleoplasmic translocation under particular types of nucleolar stresses. However, their translocations are not yet explored as universally under many stress conditions as NPM1.
Cyclin-dependent kinase inhibitor roscovitine induced both nucleolin translocation and nuclear accumulation of p53 . Nucleostemin that functions in pre-RNA processing was also translocated to the nucleoplasm under doxorubicin and Act. D treatments in neonatal rat cardiomyocytes, which occurred concurrently with p53 accumulation . D treatment and enhanced p53 stability through ARF-independent direct physical interaction with p53 .
The morphology and size of nucleoli are linked to nucleolar activity, which are inevitably altered under stress conditions, showing a variety of reorganization. The widely used descriptions of morphological alterations in nucleolar stress are based on immunostaining using fluorescence-labeled antibodies against known markers of the nucleolus, such as NPM1, fibrillarin, and UBF, that visualizes their redistribution under nucleolar stress conditions.
Typically, under Act. D treatment, these nucleolar marker proteins aggregate in different regions, migrate towards the nucleolar periphery, or even distribute to the nucleoplasm, finally forming distinct staining structures, the nucleolar caps, and spots or foci that spread in the nucleoplasm.
The Cell Nucleus
The Functional Nucleus pp Cite as. The nucleolus is the largest nuclear organelle and is the primary site of ribosome subunit biogenesis in eukaryotic cells. It is assembled around arrays of ribosomal DNA genes, forming specific chromosomal features known as nucleolar organizing regions NORs which are the sites of ribosomal DNA transcription. While the nucleolus main activity involve different steps of ribosome biogenesis, the presence of proteins with no obvious relationship with ribosome subunit production suggests additional functions for the nucleolus, such as regulation of mitosis, cell cycle progression, stress response and biogenesis of multiple ribonucleoprotein complexes. The many novel factors and separate classes of proteins identified within the nucleolus support this view that the nucleolus may perform additional functions beyond its known role in ribosome subunit biogenesis. Here we review our knowledge of the nucleolar functions and will provide a detailed picture of how the nucleolus is involved in many cellular pathways.
In cell biology , the nucleus pl. Eukaryotes usually have a single nucleus, but a few cell types, such as mammalian red blood cells , have no nuclei , and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope , a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm ; and the nuclear matrix which includes the nuclear lamina , a network within the nucleus that adds mechanical support, much like the cytoskeleton supports the cell as a whole. The cell nucleus contains all of the cell's genome , except for the small amount of mitochondrial DNA and, in plant cells, plastid DNA. Nuclear DNA is organized as multiple long linear molecules in a complex with a large variety of proteins , such as histones , to form chromosomes. The genes within these chromosomes are structured in such a way to promote cell function.
It is the command center of a eukaryotic cell and is usually the most notable cell organelle in both size and function. The key function of the nucleus is to control cell growth and multiplication. This involves regulating gene expression, initiating cellular reproduction, and storing genetic material necessary for all of these tasks. In order for a nucleus to carry out important reproductive roles and other cell activities, it needs proteins and ribosomes. It is produced in the nucleus and travels to the cytoplasm through the nuclear pores of the nuclear envelope, which you'll read about below. The shape of a nucleus varies from cell to cell but is often depicted as spherical.
Cell Stress, Vol. Abbreviations: Act. Conflict of interest statement: There is no conflict of interest. Nucleolar Stress: hallmarks, sensing mechanism and diseases.
Nucleoli also participate in the formation of signal recognition particles and play a role in the cell's response to stress.
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Она шла следом за ним точно в тумане. Коридор, выложенный кафельными плитками, довольно круто спускался вниз, и Сьюзан держалась за перила, стараясь не отставать. Воздух в помещении становился все прохладнее. Чем глубже под землю уходил коридор, тем уже он становился. Откуда-то сзади до них долетело эхо чьих-то громких, решительных шагов. Обернувшись, они увидели быстро приближавшуюся к ним громадную черную фигуру.
Да, да, - сказал он, - читайте эту благословенную надпись. Сьюзан стояла рядом, у нее подгибались колени и пылали щеки. Все в комнате оставили свои занятия и смотрели на огромный экран и на Дэвида Беккера. Профессор вертел кольцо в пальцах и изучал надпись. - Читайте медленно и точно! - приказал Джабба. - Одна неточность, и все мы погибли. Фонтейн сурово взглянул на .
Extra ribosomal functions assigned to the nucleolus include the involvement in cell cycle and cell proliferation control, stress sensing and tumor surveillance.
ГЛАВА 70 Дэвид Беккер почувствовал, что у него подкашиваются ноги. Он смотрел на девушку, понимая, что его поиски подошли к концу. Она вымыла голову и переоделась - быть может, считая, что так легче будет продать кольцо, - но в Нью-Йорк не улетела. Беккер с трудом сдерживал волнение. Его безумная поездка вот-вот закончится.