G0 phase
], cells were thought to enter G0 primarily due to environmental factors, like nutrient deprivation, that limited the resources necessary for proliferation.
Such DNA damage can occur from telomere shortening over many cell divisions as well as reactive oxygen species (ROS) exposure, oncogene activation, and cell-cell fusion.
In contrast to cellular senescence, quiescence is not a reactive event but part of the core programming of several different cell types.
The transcriptomes of several types of quiescent stem cells, such as hematopoietic, muscle, and hair follicle, have been characterized through high-throughput techniques, such as microarray and RNA sequencing.
Downregulation of mitochondrial cytochrome C also reflects the low metabolic state of quiescent stem cells.
For example, H3K4me3 and H3K27me3, are two major histone methylation patterns that form a bivalent domain and are located near transcription initiation sites.
For example, deletion of all three components of the Rb family of proteins has been shown to halt quiescence in hematopoietic stem cells.
In mouse hematopoietic stem cells, knockout of p57 and p27 leads to G0 exit through nuclear import of cyclin D1 and subsequent phosphorylation of Rb.
[11] 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 mRNAs, 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 tissue stem cells exist in a reversible, quiescent state indefinitely until being activated by external stimuli.
[13] 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 GAlert.
In muscle stem cells, mTORC1 activity has been identified to control the transition from G0 into GAlert along with signaling through the HGF receptor cMet.
[14] Often associated with aging and age-related diseases in vivo, senescent cells can be found in many renewable tissues, including the stroma, vasculature, hematopoietic system, and many epithelial organs.
Senescent fibroblasts in models of breast epithelial cell function have been found to disrupt milk protein production due to secretion of matrix metalloproteinases.
[17] 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 sarcomeres.
[19] In addition to playing a role in meiosis initiation, Rim15 has also been shown to be a critical effector for yeast cell entry into G0 in the presence of stress.
The PAS domain is a regulatory unit of the Rim15 protein that may play a role in sensing oxidative stress in yeast.
When glucose levels drop, cAMP production declines, lifting PKA's inhibition of Rim15 and allowing the yeast cell to enter G0.
Under low nitrogen conditions, Rim15 is activated to promote cell cycle arrest through inactivation of the protein kinases TORC1 and Sch9.
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 G0.
Finally, co-immunoprecipitation assays revealed that cyclin-dependent kinase 3 (cdk3) promotes G0 exit by forming a complex with cyclin C to phosphorylate Rb at S807/811.
This might suggest a possible compensation of cdk3 activity by cdk4, especially in light of the observation that G0 exit is only delayed, and not permanently inhibited, in cells lacking cdk3 but functional in cdk4.
Phosphorylation of Rb by Cdk complexes allows its dissociation from E2F transcription factors and the subsequent expression of genes necessary for G0 exit.
