Editing G0 phase

{{short description|Quiescent stage of the cell cycle in which the cell does not divide}}
{{DISPLAYTITLE:G<sub>0</sub> phase}}
[[File:Animal cell cycle-en.svg|right|thumb|350px|Mitosis in an [[animal cell]] (phases ordered counter-clockwise), with G<sub>0</sub> labeled at left.]]
[[Image:Gray626.png|thumb|right|200px|Many mammal [[cell (biology)|cells]], such as this 9x H [[neuron]], remain permanently or semipermanently in G<sub>0</sub>.]]

The '''G<sub>0</sub> phase''' describes a cellular state outside of the replicative [[cell cycle]]. Classically{{When|date=December 2023}}, cells were thought to enter G<sub>0</sub> primarily due to environmental factors, like nutrient deprivation, that limited the resources necessary for proliferation. Thus it was thought of as a '''''resting phase'''''. G<sub>0</sub> is now known to take different forms and occur for multiple reasons. For example, most adult [[neuron]]al cells, among the most metabolically active cells in the body, are fully differentiated and reside in a terminal G<sub>0</sub> phase. Neurons reside in this state, not because of stochastic or limited nutrient supply, but as a part of their developmental program.

G<sub>0</sub> was first suggested as a cell state based on early cell cycle studies. When the first studies defined the four phases of the cell cycle using radioactive labeling techniques, it was discovered that not all cells in a population [[Cell growth|proliferate]] at similar rates.<ref name="HowardPelc2009">{{cite journal| vauthors = Howard A, Pelc SR |title=Synthesis of Desoxyribonucleic Acid in Normal and Irradiated Cells and Its Relation to Chromosome Breakage|journal=International Journal of Radiation Biology and Related Studies in Physics, Chemistry and Medicine|volume=49|issue=2|year=2009|pages=207–218|issn=0020-7616|doi=10.1080/09553008514552501}}</ref> A population's "growth fraction" – or the fraction of the population that was growing – was actively proliferating, but other cells existed in a non-proliferative state. Some of these non-proliferating cells could respond to extrinsic stimuli and proliferate by re-entering the cell cycle.<ref name="Baserga2008">{{cite journal|last1=Baserga|first1=Renato | name-list-style = vanc |title=Biochemistry of the Cell Cycle: A Review |journal=Cell Proliferation|volume=1|issue=2|year=2008|pages=167–191|issn=0960-7722|doi=10.1111/j.1365-2184.1968.tb00957.x|s2cid=86353634 }}</ref> Early contrasting views either considered non-proliferating cells to simply be in an extended [[G1 phase|G<sub>1</sub> phase]] or in a cell cycle phase distinct from G<sub>1</sub> – termed G<sub>0</sub>.<ref name="Patt1963">{{cite journal | vauthors = Patt HM, Quastler H | title = Radiation effects on cell renewal and related systems | journal = Physiological Reviews | volume = 43 | issue = 3 | pages = 357–96 | date = July 1963 | pmid = 13941891 | doi = 10.1152/physrev.1963.43.3.357 }}</ref> Subsequent research pointed to a [[restriction point]] (R-point) in G<sub>1</sub> where cells can enter G<sub>0</sub> before the R-point but are committed to mitosis after the R-point.<ref name="Pardee1974">{{cite journal | vauthors = Pardee AB | title = A restriction point for control of normal animal cell proliferation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 4 | pages = 1286–90 | date = April 1974 | pmid = 4524638 | pmc = 388211 | doi = 10.1073/pnas.71.4.1286 | bibcode = 1974PNAS...71.1286P | doi-access = free }}</ref> These early studies provided evidence for the existence of a G<sub>0</sub> state to which access is restricted. These cells that do not divide further exit G<sub>1</sub> phase to enter an inactive stage called '''quiescent stage.'''

==Diversity of G<sub>0</sub> states==
[[File:Human karyotype with bands and sub-bands.png|thumb|250px|Schematic [[karyogram]] of the human chromosomes, showing their usual state in the G<sub>0</sub> and G<sub>1</sub> phase of the cell cycle. At top center it also shows the chromosome 3 pair after having undergone [[DNA synthesis]], occurring in the [[S phase]] (annotated as S) of the cell cycle. This interval includes the [[G2 phase|G<sub>2</sub> phase]] and [[metaphase]] (annotated as "Meta.").<br>{{further|Karyotype}}]]
Three G<sub>0</sub> states exist and can be categorized as either reversible ([[wikt:quiescent|quiescent]]) or irreversible ([[Cellular senescence|senescent]] and [[Cellular differentiation|differentiated]]). Each of these three states can be entered from the G<sub>1</sub> phase before the cell commits to the next round of the cell cycle. Quiescence refers to a reversible G<sub>0</sub> state where subpopulations of cells reside in a 'quiescent' state before entering the cell cycle after activation in response to extrinsic signals. Quiescent cells are often identified by low [[RNA]] content, lack of cell proliferation markers, and increased label retention indicating low cell turnover.<ref name="Hüttmann2001">{{cite journal|last1=Hüttmann|first1=A|title=Functional heterogeneity within rhodamine123lo Hoechst33342lo/sp primitive hemopoietic stem cells revealed by pyronin Y|journal=Experimental Hematology|volume=29|issue=9|year=2001|pages=1109–1116|issn=0301-472X|doi=10.1016/S0301-472X(01)00684-1|pmid=11532352|doi-access=free}}</ref><ref name="FukadaUezumi2007">{{cite journal | vauthors = Fukada S, Uezumi A, Ikemoto M, Masuda S, Segawa M, Tanimura N, Yamamoto H, Miyagoe-Suzuki Y, Takeda S | title = Molecular signature of quiescent satellite cells in adult skeletal muscle | journal = Stem Cells | volume = 25 | issue = 10 | pages = 2448–59 | date = October 2007 | pmid = 17600112 | doi = 10.1634/stemcells.2007-0019 | doi-access = free }}</ref> [[Senescence]] is distinct from quiescence because senescence is an irreversible state that cells enter in response to DNA damage or degradation that would make a cell's progeny nonviable. Such [[DNA damage (naturally occurring)|DNA damage]] can occur from [[Telomere#Shortening|telomere shortening]] over many cell divisions as well as reactive oxygen species (ROS) exposure, oncogene activation, and cell-cell fusion. While senescent cells can no longer replicate, they remain able to perform many normal cellular functions.<ref>{{cite journal | vauthors = Hayflick L, Moorhead PS | title = The serial cultivation of human diploid cell strains | journal = Experimental Cell Research | volume = 25 | issue = 3 | pages = 585–621 | date = December 1961 | pmid = 13905658 | doi = 10.1016/0014-4827(61)90192-6 }}</ref><ref>{{cite journal | vauthors = Campisi J | title = Aging, cellular senescence, and cancer | journal = Annual Review of Physiology | volume = 75 | pages = 685–705 | date = February 2013 | pmid = 23140366 | pmc = 4166529 | doi = 10.1146/annurev-physiol-030212-183653 }}</ref><ref>{{cite journal | vauthors = Rodier F, Campisi J | title = Four faces of cellular senescence | journal = The Journal of Cell Biology | volume = 192 | issue = 4 | pages = 547–56 | date = February 2011 | pmid = 21321098 | pmc = 3044123 | doi = 10.1083/jcb.201009094 }}</ref><ref>{{cite journal | vauthors = Burton DG, Krizhanovsky V | title = Physiological and pathological consequences of cellular senescence | journal = Cellular and Molecular Life Sciences | volume = 71 | issue = 22 | pages = 4373–86 | date = November 2014 | pmid = 25080110 | pmc = 4207941 | doi = 10.1007/s00018-014-1691-3 }}</ref> Senescence is often a biochemical alternative to the self-destruction of such a damaged cell by [[apoptosis]]. In contrast to cellular senescence, quiescence is not a reactive event but part of the core programming of several different cell types. Finally, differentiated cells are stem cells that have progressed through a differentiation program to reach a mature – terminally differentiated – state. Differentiated cells continue to stay in G<sub>0</sub> and perform their main functions indefinitely.

==<span id="Characteristics of Quiescent Stem Cells"></span>Characteristics of quiescent stem cells==
===Transcriptomes===
The [[transcriptomes]] of several types of quiescent stem cells, such as [[hematopoietic]], muscle, and hair follicle, have been characterized through [[high throughput biology|high-throughput]] techniques, such as [[microarray]] and [[RNA sequencing]]. Although variations exist in their individual transcriptomes, most quiescent tissue stem cells share a common pattern of gene expression that involves downregulation of cell cycle progression genes, such as [[cyclin A2]], [[cyclin B1]], [[cyclin E2]], and [[survivin]], and upregulation of genes involved in the regulation of transcription and stem cell fate, such as [[FOXO3]] and [[EZH1]]. Downregulation of mitochondrial [[cytochrome C]] also reflects the low metabolic state of quiescent stem cells.<ref name="CheungRando2013">{{cite journal | vauthors = Cheung TH, Rando TA | title = Molecular regulation of stem cell quiescence | journal = Nature Reviews. Molecular Cell Biology | volume = 14 | issue = 6 | pages = 329–40 | date = June 2013 | pmid = 23698583 | pmc = 3808888 | doi = 10.1038/nrm3591 }}</ref>

===Epigenetic===
Many quiescent stem cells, particularly [[adult stem cells]], also share similar [[epigenetic]] patterns. For example, [[H3K4me3]] and [[H3K27me3]], are two major [[histone]] methylation patterns that form a bivalent domain and are located near transcription initiation sites. These epigenetic markers have been found to regulate lineage decisions in embryonic stem cells as well as control quiescence in hair follicle and muscle stem cells via [[chromatin]] modification.<ref name="CheungRando2013"/>

== <span id="&nbsp;Regulation of Quiescence"></span>Regulation of quiescence ==

=== <span id="&nbsp;Cell Cycle Regulators"></span>Cell cycle regulators ===
Functional [[tumor suppressor genes]], particularly [[p53]] and [[Rb gene]], are required to maintain stem cell quiescence and prevent exhaustion of the [[progenitor cell]] pool through excessive divisions. For example, deletion of all three components of the Rb family of proteins has been shown to halt quiescence in hematopoietic stem cells. Lack of p53 has been shown to prevent differentiation of these stem cells due to the cells' inability to exit the cell cycle into the G<sub>0</sub> phase. In addition to p53 and Rb, [[cyclin dependent kinase]] inhibitors (CKIs), such as [[p21]], [[CDKN1B|p27]], and [[p57 (gene)|p57]], are also important for maintaining quiescence. In mouse hematopoietic stem cells, knockout of p57 and p27 leads to G<sub>0</sub> exit through nuclear import of [[cyclin D1]] and subsequent [[phosphorylation]] of Rb. Finally, the [[Notch signaling pathway]] has been shown to play an important role in maintenance of quiescence.<ref name="CheungRando2013"/>

===Post-transcriptional regulation===
Post-transcriptional regulation of gene expression via [[miRNA]] synthesis has been shown to play an equally important role in the maintenance of stem cell quiescence. miRNA strands bind to the 3′ untranslated region ([[3′ UTR]]) of target [[mRNA]]s, preventing their translation into functional proteins. The length of the 3′ UTR of a gene determines its ability to bind to miRNA strands, thereby allowing regulation of quiescence. Some examples of miRNA's in stem cells include miR-126, which controls the [[PI3K/AKT/mTOR pathway]] in hematopoietic stem cells, miR-489, which suppresses the DEK [[oncogene]] in muscle stem cells, and miR-31, which regulates [[Myf5]] in muscle stem cells. miRNA sequestration of mRNA within [[ribonucleoprotein]] complexes allows quiescent cells to store the mRNA necessary for quick entry into the [[G1 phase]].<ref name="CheungRando2013"/>

=== <span id="&nbsp;Response to Stress"></span>Response to stress ===
Stem cells that have been quiescent for a long time often face various environmental stressors, such as [[oxidative stress]]. However, several mechanisms allow these cells to respond to such stressors. For example, the [[FOXO]] transcription factors respond to the presence of [[reactive oxygen species]] (ROS) while [[HIF1A]] and [[LKB1]] respond to [[Hypoxia (medical)|hypoxic]] conditions. In hematopoietic stem cells, [[autophagy]] is induced to respond to metabolic stress.<ref name="CheungRando2013"/>

==Examples of reversible G<sub>0</sub> phase==
===Tissue stem cells===
Stem cells are cells with the unique ability to produce differentiated [[Cell division|daughter cells]] and to preserve their stem cell identity through self-renewal.<ref name="Weissman2000">{{cite journal | vauthors = Weissman IL | title = Stem cells: units of development, units of regeneration, and units in evolution | journal = Cell | volume = 100 | issue = 1 | pages = 157–68 | date = January 2000 | pmid = 10647940 | doi = 10.1016/S0092-8674(00)81692-X | doi-access = free }}</ref>
In mammals, most adult tissues contain [[Adult stem cell|tissue-specific stem cells]] that reside in the tissue and proliferate to maintain homeostasis for the lifespan of the organism. These cells can undergo immense proliferation in response to tissue damage before differentiating and engaging in regeneration. Some tissue stem cells exist in a reversible, quiescent state indefinitely until being activated by external stimuli. Many different types of tissue stem cells exist, including [[Myosatellite cell|muscle stem cells]] (MuSCs), [[neural stem cell]]s (NSCs), [[Adult stem cell#Intestinal stem cells|intestinal stem cells]] (ISCs), and many others.

Stem cell quiescence has been recently suggested to be composed of two distinct functional phases, G<sub>0</sub> and an 'alert' phase termed G<sub>Alert</sub>.<ref name="RodgersKing2014">{{cite journal | vauthors = Rodgers JT, King KY, Brett JO, Cromie MJ, Charville GW, Maguire KK, Brunson C, Mastey N, Liu L, Tsai CR, Goodell MA, Rando TA | title = mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert) | journal = Nature | volume = 510 | issue = 7505 | pages = 393–6 | date = June 2014 | pmid = 24870234 | pmc = 4065227 | doi = 10.1038/nature13255 | bibcode = 2014Natur.510..393R }}</ref>
Stem cells are believed to actively and reversibly transition between these phases to respond to injury stimuli and seem to gain enhanced tissue regenerative function in G<sub>Alert</sub>. Thus, transition into G<sub>Alert</sub> has been proposed as an adaptive response that enables stem cells to rapidly respond to injury or stress by priming them for cell cycle entry. In muscle stem cells, [[mTORC1]] activity has been identified to control the transition from G<sub>0</sub> into G<sub>Alert</sub> along with signaling through the [[Hepatocyte growth factor|HGF]] receptor [[C-Met|cMet]].<ref name="RodgersKing2014"/>

===Mature hepatocytes===
While a reversible quiescent state is perhaps most important for tissue stem cells to respond quickly to stimuli and maintain proper homeostasis and regeneration, reversible G<sub>0</sub> phases can be found in non-stem cells such as mature hepatocytes.<ref name="Fausto2004">{{cite journal | vauthors = Fausto N | title = Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells | journal = Hepatology | volume = 39 | issue = 6 | pages = 1477–87 | date = June 2004 | pmid = 15185286 | doi = 10.1002/hep.20214 | doi-access = free }}</ref> Hepatocytes are typically quiescent in normal livers but undergo limited replication (less than 2 cell divisions) during liver regeneration after partial hepatectomy. However, in certain cases, hepatocytes can experience immense proliferation (more than 70 cell divisions) indicating that their proliferation capacity is not hampered by existing in a reversible quiescent state.<ref name="Fausto2004"/>

==Examples of irreversible G<sub>0</sub> phase==
===Senescent cells===
Often associated with aging and age-related diseases in vivo, senescent cells can be found in many renewable tissues, including the [[stroma (tissue)|stroma]], [[vasculature]], [[hematopoietic system]], and many [[epithelial]] organs. Resulting from accumulation over many cell divisions, senescence is often seen in age-associated degenerative phenotypes. Senescent fibroblasts in models of breast epithelial cell function have been found to disrupt milk protein production due to secretion of matrix [[metalloproteinase]]s.<ref name="DownwardCoppé2008">{{cite journal | vauthors = Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J | title = Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor | journal = PLOS Biology | volume = 6 | issue = 12 | pages = 2853–68 | date = December 2008 | pmid = 19053174 | pmc = 2592359 | doi = 10.1371/journal.pbio.0060301 | doi-access = free }}</ref>
Similarly, senescent pulmonary artery smooth muscle cells caused nearby smooth muscle cells to proliferate and migrate, perhaps contributing to hypertrophy of pulmonary arteries and eventually pulmonary hypertension.<ref name="NoureddineGary-Bobo2011">{{cite journal | vauthors = Noureddine H, Gary-Bobo G, Alifano M, Marcos E, Saker M, Vienney N, Amsellem V, Maitre B, Chaouat A, Chouaid C, Dubois-Rande JL, Damotte D, Adnot S | title = Pulmonary artery smooth muscle cell senescence is a pathogenic mechanism for pulmonary hypertension in chronic lung disease | journal = Circulation Research | volume = 109 | issue = 5 | pages = 543–53 | date = August 2011 | pmid = 21719760 | pmc = 3375237 | doi = 10.1161/CIRCRESAHA.111.241299 }}</ref>

===Differentiated muscle===
During skeletal [[myogenesis]], cycling progenitor cells known as [[myoblast]]s differentiate and fuse together into non-cycling muscle cells called myocytes that remain in a terminal G<sub>0</sub> phase.<ref>page 395, Biology, Fifth Edition, Campbell, 1999</ref> As a result, the fibers that make up [[skeletal muscle]] (myofibers) are cells with multiple nuclei, referred to as myonuclei, since each myonucleus originated from a single myoblast. Skeletal muscle cells continue indefinitely to provide contractile force through simultaneous contractions of cellular structures called [[sarcomere]]s. Importantly, these cells are kept in a terminal G<sub>0</sub> phase since disruption of muscle fiber structure after myofiber formation would prevent proper transmission of force through the length of the muscle. Muscle growth can be stimulated by growth or injury and involves the recruitment of muscle stem cells – also known as satellite cells – out of a reversible quiescent state. These stem cells differentiate and fuse to generate new muscle fibers both in parallel and in series to increase force generation capacity.

[[Cardiac muscle]] is also formed through myogenesis but instead of recruiting stem cells to fuse and form new cells, heart muscle cells – known as [[cardiomyocyte]]s – simply increase in size as the heart grows larger. Similarly to skeletal muscle, if cardiomyocytes had to continue dividing to add muscle tissue the contractile structures necessary for heart function would be disrupted.

===Differentiated bone===
Of the four major types of bone cells, [[osteocyte]]s are the most common and also exist in a terminal G<sub>0</sub> phase. Osteocytes arise from osteoblasts that are trapped within a self-secreted matrix. While osteocytes also have reduced synthetic activity, they still serve bone functions besides generating structure. Osteocytes work through various mechanosensory mechanisms to assist in the routine turnover over bony matrix.

===Differentiated nerve===
Outside of a few [[neurogenesis|neurogenic]] niches in the brain, most [[neuron]]s are fully differentiated and reside in a terminal G<sub>0</sub> phase. These fully differentiated neurons form [[synapse]]s where electrical signals are transmitted by [[axon]]s to the [[dendrite]]s of nearby neurons. In this G<sub>0</sub> state, neurons continue functioning until senescence or apoptosis. Numerous studies have reported accumulation of [[DNA damage (naturally occurring)|DNA damage]] with age, particularly [[DNA oxidation|oxidative damage]], in the mammalian [[brain]].<ref name=Bernstein2008>Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) [[Nova Science Publishers, Inc.]], New York, Chapter 1, pp. 1–47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 {{Webarchive|url=https://web.archive.org/web/20141025091740/https://www.novapublishers.com/catalog/product_info.php?products_id=43247 |date=2014-10-25 }} {{ISBN|1604565810}} {{ISBN|978-1604565812}}</ref>

== <span id=" Mechanism of G0 Entry"></span>Mechanism of G<sub>0</sub> entry ==

=== <span id=" The Role of Rim15"></span>Role of Rim15 ===
Rim15 was first discovered to play a critical role in initiating [[meiosis]] in [[diploid]] yeast cells. Under conditions of low glucose and nitrogen, which are key nutrients for the survival of yeast, diploid yeast cells initiate meiosis through the activation of early meiotic-specific genes (EMGs). The expression of EMGs is regulated by Ume6. Ume6 recruits the [[histone deacetylases]], [[Rpd3]] and Sin3, to repress EMG expression when glucose and nitrogen levels are high, and it recruits the EMG transcription factor Ime1 when glucose and nitrogen levels are low. Rim15, named for its role in the regulation of an EMG called IME2, displaces Rpd3 and Sin3, thereby allowing Ume6 to bring Ime1 to the promoters of EMGs for meiosis initiation.<ref name="Swinnenetal2006">{{cite journal | vauthors = Swinnen E, Wanke V, Roosen J, Smets B, Dubouloz F, Pedruzzi I, Cameroni E, De Virgilio C, Winderickx J | title = Rim15 and the crossroads of nutrient signalling pathways in Saccharomyces cerevisiae | journal = Cell Division | volume = 1 | issue = 3 | pages = 3 | date = April 2006 | pmid = 16759348 | pmc = 1479807 | doi = 10.1186/1747-1028-1-3 | doi-access = free }}</ref>

In addition to playing a role in meiosis initiation, Rim15 has also been shown to be a critical effector for yeast cell entry into G<sub>0</sub> in the presence of stress. Signals from several different nutrient signaling pathways converge on Rim15, which activates the transcription factors, Gis1, Msn2, and Msn4. Gis1 binds to and activates promoters containing post-[[diauxic growth]] shift (PDS) elements while Msn2 and Msn4 bind to and activate promoters containing stress-[[response elements]] (STREs). Although it is not clear how Rim15 activates Gis1 and Msn2/4, there is some speculation that it may directly phosphorylate them or be involved in chromatin remodeling. Rim15 has also been found to contain a [[PAS domain]] at its [[N terminal]], making it a newly discovered member of the PAS [[kinase]] family. The PAS domain is a regulatory unit of the Rim15 protein that may play a role in sensing oxidative stress in yeast.<ref name="Swinnenetal2006"/>

=== <span id=" Nutrient Signaling Pathways"></span>Nutrient signaling pathways ===

====Glucose====
Yeast grows exponentially through [[fermentation]] of glucose. When glucose levels drop, yeast shift from fermentation to [[cellular respiration]], metabolizing the fermentative products from their exponential growth phase. This shift is known as the diauxic shift after which yeast enter G<sub>0</sub>. When glucose levels in the surroundings are high, the production of [[cyclic adenosine monophosphate|cAMP]] through the RAS-cAMP-PKA pathway (a [[cAMP-dependent pathway]]) is elevated, causing [[protein kinase A]] (PKA) to inhibit its downstream target Rim15 and allow cell proliferation. When glucose levels drop, cAMP production declines, lifting PKA's inhibition of Rim15 and allowing the yeast cell to enter G<sub>0</sub>.<ref name="Swinnenetal2006"/>

====Nitrogen====
In addition to glucose, the presence of nitrogen is crucial for yeast proliferation. Under low nitrogen conditions, Rim15 is activated to promote cell cycle arrest through inactivation of the protein kinases [[TORC1]] and Sch9. While TORC1 and Sch9 belong to two separate pathways, namely the TOR and Fermentable Growth Medium induced pathways respectively, both protein kinases act to promote cytoplasmic retention of Rim15. Under normal conditions, Rim15 is anchored to the cytoplasmic [[14-3-3 protein]], Bmh2, via phosphorylation of its Thr1075. TORC1 inactivates certain [[phosphatases]] in the cytoplasm, keeping Rim15 anchored to Bmh2, while it is thought that Sch9 promotes Rim15 cytoplasmic retention through phosphorylation of another 14-3-3 binding site close to Thr1075. When extracellular nitrogen is low, TORC1 and Sch9 are inactivated, allowing dephosphorylation of Rim15 and its subsequent transport to the nucleus, where it can activate transcription factors involved in promoting cell entry into G<sub>0</sub>. It has also been found that Rim15 promotes its own export from the nucleus through [[autophosphorylation]].<ref name="Swinnenetal2006"/>

====Phosphate====
Yeast cells respond to low extracellular phosphate levels by activating genes that are involved in the production and upregulation of inorganic phosphate. The PHO pathway is involved in the regulation of phosphate levels. Under normal conditions, the yeast [[cyclin-dependent kinase complex]], Pho80-Pho85, inactivates the [[Pho4]] transcription factor through phosphorylation. However, when phosphate levels drop, Pho81 inhibits Pho80-Pho85, allowing Pho4 to be active. When phosphate is abundant, Pho80-Pho85 also inhibits the nuclear pool of Rim 15 by promoting phosphorylation of its Thr1075 Bmh2 binding site. Thus, Pho80-Pho85 acts in concert with Sch9 and TORC1 to promote cytoplasmic retention of Rim15 under normal conditions.<ref name="Swinnenetal2006"/>

== <span id=" Mechanism of G0 Exit"></span>Mechanism of G<sub>0</sub> exit ==

===Cyclin C/Cdk3 and Rb===
The transition from G<sub>1</sub> to [[S phase]] is promoted by the inactivation of Rb through its progressive [[hyperphosphorylation]] by the [[Cyclin D/Cdk4]] and [[Cyclin E]]/Cdk2 complexes in late G<sub>1</sub>. An early observation that loss of Rb promoted cell cycle re-entry in G<sub>0</sub> cells suggested that Rb is also essential in regulating the G<sub>0</sub> to G<sub>1</sub> transition in quiescent cells.<ref name="Sage2004">{{cite journal|last1=Sage|first1=Julien|title=Cyclin C Makes an Entry into the Cell Cycle|journal=Developmental Cell|volume=6|issue=5|year=2004|pages=607–608|doi=10.1016/S1534-5807(04)00137-6|pmid=15130482|doi-access=free}}</ref> Further observations revealed that levels of [[cyclin C]] mRNA are highest when human cells exit G<sub>0</sub>, suggesting that cyclin C may be involved in Rb phosphorylation to promote cell cycle re-entry of G<sub>0</sub> arrested cells. [[Immunoprecipitation]] kinase assays revealed that cyclin C has Rb kinase activity. Furthermore, unlike cyclins D and E, cyclin C's Rb kinase activity is highest during early G<sub>1</sub> and lowest during late G<sub>1</sub> and S phases, suggesting that it may be involved in the G<sub>0</sub> to G<sub>1</sub> transition. The use of [[fluorescence-activated cell sorting]] to identify G<sub>0</sub> cells, which are characterized by a high DNA to RNA ratio relative to G<sub>1</sub> cells, confirmed the suspicion that cyclin C promotes G<sub>0</sub> exit as repression of endogenous cyclin C by [[RNAi]] in mammalian cells increased the proportion of cells arrested in G<sub>0</sub>. Further experiments involving mutation of Rb at specific phosphorylation sites showed that cyclin C phosphorylation of Rb at S807/811 is necessary for G<sub>0</sub> exit. It remains unclear, however, whether this phosphorylation pattern is sufficient for G<sub>0</sub> exit. Finally, co-immunoprecipitation assays revealed that [[cyclin-dependent kinase 3]] (cdk3) promotes G<sub>0</sub> exit by forming a complex with cyclin C to phosphorylate Rb at S807/811. Interestingly, S807/811 are also targets of cyclin D/cdk4 phosphorylation during the G<sub>1</sub> to S transition. This might suggest a possible compensation of cdk3 activity by cdk4, especially in light of the observation that G<sub>0</sub> exit is only delayed, and not permanently inhibited, in cells lacking cdk3 but functional in cdk4. Despite the overlap of phosphorylation targets, it seems that cdk3 is still necessary for the most effective transition from G<sub>0</sub> to G<sub>1</sub>.<ref name="RenRollins2004">{{cite journal | vauthors = Ren S, Rollins BJ | title = Cyclin C/cdk3 promotes Rb-dependent G0 exit | journal = Cell | volume = 117 | issue = 2 | pages = 239–51 | date = April 2004 | pmid = 15084261 | doi = 10.1016/S0092-8674(04)00300-9 | doi-access = free }}</ref>

===Rb and G<sub>0</sub> exit===
Studies suggest that Rb repression of the [[E2F]] family of transcription factors regulates the G<sub>0</sub> to G<sub>1</sub> transition just as it does the G<sub>1</sub> to S transition. Activating E2F complexes are associated with the recruitment of [[histone acetyltransferases]], which activate gene expression necessary for G<sub>1</sub> entry, while [[E2F4]] complexes recruit histone deacetylases, which repress gene expression. Phosphorylation of Rb by Cdk complexes allows its dissociation from E2F transcription factors and the subsequent expression of genes necessary for G<sub>0</sub> exit. Other members of the Rb [[pocket protein family]], such as p107 and p130, have also been found to be involved in G<sub>0</sub> arrest. p130 levels are elevated in G<sub>0</sub> and have been found to associate with E2F-4 complexes to repress transcription of E2F target genes. Meanwhile, p107 has been found to rescue the cell arrest phenotype after loss of Rb even though p107 is expressed at comparatively low levels in G<sub>0</sub> cells. Taken together, these findings suggest that Rb repression of E2F transcription factors promotes cell arrest while phosphorylation of Rb leads to G<sub>0</sub> exit via derepression of E2F target genes.<ref name="Sage2004"/> In addition to its regulation of E2F, Rb has also been shown to suppress [[RNA polymerase I]] and [[RNA polymerase III]], which are involved in [[rRNA]] synthesis. Thus, phosphorylation of Rb also allows activation of rRNA synthesis, which is crucial for protein synthesis upon entry into G<sub>1</sub>.<ref name="RenRollins2004"/>

== References ==
{{Reflist}}

{{Cell cycle}}

{{DEFAULTSORT:G0 Phase}}
[[Category:Cell cycle]]