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Regulation of Cell Cycle Entry and Exit: A Single Cell Perspective

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The transition between proliferating and quiescent states must be carefully regulated to ensure that cells divide to create the cells an organism needs only at the appropriate time and place. Cyclin‐dependent kinases (CDKs) are critical for both transitioning cells from one cell cycle state to the next, and for regulating whether cells are proliferating or quiescent. CDKs are regulated by association with cognate cyclins, activating and inhibitory phosphorylation events, and proteins that bind to them and inhibit their activity. The substrates of these kinases, including the retinoblastoma protein, enforce the changes in cell cycle status. Single cell analysis has clarified that competition among factors that activate and inhibit CDK activity leads to the cell's decision to enter the cell cycle, a decision the cell makes before S phase. Signaling pathways that control the activity of CDKs regulate the transition between quiescence and proliferation in stem cells, including stem cells that generate muscle and neurons. © 2020 American Physiological Society. Compr Physiol 10:317‐344, 2020.

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Figure 1. Figure 1. Molecular changes in proliferating versus quiescent cells. A schematic of quiescent cells and a summary of the molecular changes are provided. Compared with proliferating cells, quiescent cells have lower levels of receptor tyrosine kinase and MAP kinase signaling, lower cyclin D levels, lower CDK activity, higher levels of cyclin‐dependent kinase inhibitor levels, lower levels of retinoblastoma phosphorylation, and reduced E2F activity. The activity of mitogens and integrins can shift quiescent cells to proliferation. Proliferating cells have higher levels of receptor tyrosine kinase and MAP kinase activity, increased cyclin D levels, increased CDK activity, lower levels of cyclin‐dependent kinase inhibitors, increased retinoblastoma phosphorylation, and increased E2F activity. The notch signaling pathway can promote the quiescent state.

Figure 1. Molecular changes in proliferating versus quiescent cells. A schematic of quiescent cells and a summary of the molecular changes are provided. Compared with proliferating cells, quiescent cells have lower levels of receptor tyrosine kinase and MAP kinase signaling, lower cyclin D levels, lower CDK activity, higher levels of cyclin‐dependent kinase inhibitor levels, lower levels of retinoblastoma phosphorylation, and reduced E2F activity. The activity of mitogens and integrins can shift quiescent cells to proliferation. Proliferating cells have higher levels of receptor tyrosine kinase and MAP kinase activity, increased cyclin D levels, increased CDK activity, lower levels of cyclin‐dependent kinase inhibitors, increased retinoblastoma phosphorylation, and increased E2F activity. The notch signaling pathway can promote the quiescent state.
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Teaching Material

Hilary A. Coller. Regulation of cell cycle entry and exit: a single cell perspective. Compr Physiol 10 : 2020, 317-344.

Didactic Synopsis

Major Teaching Points:

• The restriction point is a point of no return in the cell cycle: after the restriction point, cells will continue to cycle even if pro-proliferative signals are withdrawn.

• Cyclin-dependent kinases are activated by cognate cyclins to phosphorylate target proteins.

• Cyclins are tagged with ubiquitins that mark them for degradation at the proteasome.

• The anaphase promoting complex and the SCF complex add ubiquitins to cell cycle proteins and regulate their degradation.

• Cyclin-dependent kinases are regulated by activating and inhibitory phosphorylation events.

• The CIP and INK4 families of cyclin-dependent kinase inhibitors arrest the cell cycle.

• The retinoblastoma protein is a substrate of cyclin-dependent kinases; when it is hyperphosphorylated, it releases E2F transcription factors that activate transcription of cell cycle-promoting target genes.

• Single cell analysis with E2F reporters reveals that E2F signaling is bimodal: some cells have low E2F activity and some cells have high activity, with few cells having intermediate levels.

• Single cell analysis reveals that E2F signaling demonstrates hysteresis: E2F signaling can be "on" or "off" when cells are stimulated with the same amount of serum depending on whether the cells were quiescent or proliferating prior to treatment.

• Real-time monitoring of a population of cycling cells revealed that cells with low CDK activity fail to divide, and the levels of cyclin-dependent kinase inhibitor p21 in each cell predicts whether that cell will continue to divide or arrest.

• The quiescent versus activated state of muscle stem cells is regulated by multiple signaling pathways including fibroblast growth factor, hepatocyte growth factor, ERK, notch and integrin signaling.

• Muscle stem cells can be in a G0 quiescent state or a Galert state depending on mTORC1 activity.

• Neural stem cells can be activated from a quiescent to an active state by signaling pathways that include FGF, EGF, and notch.

• Single cell sequencing analysis of neural stem cells revealed a continuum of activation states between quiescent and fully activated.


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How to Cite

Hilary A. Coller. Regulation of Cell Cycle Entry and Exit: A Single Cell Perspective. Compr Physiol 2019, 10: 317-344. doi: 10.1002/cphy.c190014