The essence of yeast quiescence

Like all microorganisms, yeast cells spend most of their natural lifetime in a reversible, quiescent state that is primarily induced by limitation for essential nutrients. Substantial progress has been made in defining the features of quiescent cells and the nutrient-signaling pathways that shape these features. A view that emerges from the wealth of new data is that yeast cells dynamically configure the quiescent state in response to nutritional challenges by using a set of key nutrient-signaling pathways, which (1) regulate pathway-specific effectors, (2) converge on a few regulatory nodes that bundle multiple inputs to communicate unified, graded responses, and (3) mutually modulate their competences to transmit signals. Here, I present an overview of our current understanding of the architecture of these pathways, focusing on how the corresponding core signaling protein kinases (i.e. PKA, TORC1, Snf1, and Pho85) are wired to ensure an adequate response to nutrient starvation, which enables cells to tide over decades, if not centuries, of famine.     

Suspended animation,diapause and quiescence

Developing organisms require nutrients to support cell division vital for growth and development. An adaptation to stress, used by many organisms, is to reversibly enter an arrested state by reducing energy-requiring processes, such as development and cell division. This “wait it out” approach to survive stress until the environment is conductive for growth and development is used by many metazoans. Much is known about the molecular regulation of cell division, metazoan development and responses to environmental stress. However, how these biological processes intersect is less understood. Here, we review studies conducted in Caenorhabditis elegans that investigate how stresses such as oxygen deprivation (hypoxia and anoxia), exogenous chemicals or starvation affect cellular processes in the embryo, larvae or adult germline. Using C. elegans to identify how stress signals biological arrest can help in our understanding of evolutionary pressures as well as human health-related issues.     

Induction of quiescence by differentiating agents

The growth fraction of cancer cells, estimated by the monoclonal antibody Ki-67 labelling, and DNA content were determined simultaneously en K562 human leukemic cells by flow cytometry. Adriamycin, aclacinomycin A and fagaronine induced differentiation, as assessed by benzidine staining and glycophorin A expression. These drugs decreases the fraction of Ki-67 positive cells, Ki-67 negative cells displayed a G1, but also a G2 and a S DNA content in different proportions, indicating that induction of quiescent cells by differentiating agents is not a uniform process and is worthy of interest.     

Staying alive: Metabolic adaptations to quiescence

Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. In some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the PI3Kinase/TOR signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOR kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. In this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems.     

Calcium-induced quiescence in reactivated sea urchin sperm

Sperm flagella of the sea urchin Tripneustes gratilla beat with asymmetrical bending waves after demembranation with Triton X-100 in the presence of EGTA and reactivation at pH 8.1 with 1 mM ATP in the presence of 2 mM MgSO4. Addition of 0.1--0.2 mM free Ca2+ to these reactivated sperm induces 70--95% of them to become quiescent. This quiescence can be reversed by reduction of the free Ca2% concentration with EGTA, or by dilution to reduce the MgATP2- concentration below 0.3 mM. The quiescent waveform is characterized by a sharp principal bend of approximately 5.6 rad in the proximal region of the flagellum, a slight reverse bend in the midregion that averages approximately 0.3 rad, and a principal bend of approximately 1.1 rad in the tip. The quiescent sperm are highly fragile mechanically, and disruption, including microtubule sliding, occurs spontaneously at a slow rate upon standing or immediately upon gentle agitation. Mild digestion by trypsin causes a gradual appearance of normal, symmetrical flagellar beating. Addition of increasing concentrations of vanadate to quiescent sperm causes a graded decrease in the proximal bend angle, with 50 micrometers vanadate reducing it to approximately 2.6 rad. In the presence of 0.1 mM free Ca2% and 10 micrometers vanadate, a characteristic, crescented stationary bend is induced in the demembranated sperm, without intermediate oscillatory beating, by the addition of either 0.1 or 1 mM ATP. In the absence of vanadate, these two concentrations of ATP produce asymmetric beating and quiescence, respectively. The results support the hypothesis that quiescence in live sperm is induced by an elevated concentration of intracellular Ca2%. In addition, they demonstrate that bending can occur in flagella in which oscillatory beating is inhibited and emphasize the close relationship between asymmetric beating and quiescence.     

The cell fate: senescence or quiescence

Senescence and quiescence are frequently used as interchangeable terms in the literature unwittingly. Despite the fact that common molecules play role in decision of cell cycle arrest, senescent and quiescent cells have some distinctive phenotypes at both molecular and morphological levels. Thus, in this review we summarized the features of senescence and quiescence with respect to visual characteristics and prominent key molecules. A PubMed research was conducted for the key words; “senescence”, “quiescence” and “cell cycle arrest”. The results which are related to cell cycle control were selected. The selection criteria of the target articles used for this review included also key cell cycle molecules such as p53, pRB, p21, p16, mTOR, p27, etc. The results were not evaluated statistically. The mechanistic target of rapamycin (mTOR) has been claimed to be key molecule in switching on/off senescence/quiescence. Specifically, although maximal p53 activation blocks mTOR and causes quiescence, partial p53 activation sustains mTOR activity and causes senescence subsequently. In broader perspective, quiescence occurs due to lack of nutrition and growth factors whereas senescence takes place due to aging and serious DNA damages. Contrary to quiescence, senescence is a degenerative process ensuing a certain cell death. We highlighted several differences between senescence and quiescence and their key molecules in this review. Whereas quiescence (cell cycle arrest) is only one half of the senescence, the other half is growth stimulation which causes actual senescence phenotype.     

mTORC1 signaling governs hematopoietic stem cell quiescence

The stringent regulation of hematopoietic stem cell (HSC) quiescence versus cell cycle progression is essential for the preservation of a pool of long-term self-renewing cells and vital for sustaining an adequate supply of all blood lineages throughout life. Cell growth, the process that is mass increase, serves as a trigger for cell cycle progression and is regulated predominantly by mammalian target of rapamycin complex 1 (mTORC1) signaling. Emerging data from various mice models show deletion of several mTORC1 negative regulators, including PTEN, TSC1, PML and Fbxw7 result in similar HSC phenotypes characterized as HSC hyper-proliferation and subsequent exhaustion, and defective repopulating potential. Further pharmacological approaches show that PTEN, TSC1 and PML regulate HSC maintenance through mTORC1. mTORC1-mediated cell growth regulatory circuits thus plays a critical role in the regulation of HSC quiescence.     

Small RNA-mediated quiescence of transposable elements in animals

Transposable elements (TEs) are major components of the intergenic regions of the genome. However, TE transposition has the potential to threaten the reproductive fitness of the organism; therefore, organisms have evolved specialized molecular systems to sense and repress the expression of TEs to stop them from jumping to other genomic loci. Emerging evidence suggests that Argonaute proteins play a critical role in this process, in collaboration with two types of cellular small RNAs: PIWI-interacting RNAs (piRNAs) of the germline and endogenous small interfering RNAs (endo-siRNAs) of the soma, both of which are transcribed from TEs themselves.