Contributed by Steve Anderson, Ph.D.
Cell cycle progression and proliferation have been well-studied, while much less attention has been given to cellular quiescence corresponding to the G0 phase of the cell cycle. Recent studies have determined that G0 is not a single state, but a spectrum of quiescent states associated with an active transcriptional program2,4. In a new study, Yao and colleagues examined the factors that control entry into and exit from quiescence and commitment to cell cycle progression2. Being able to control this transition may be an untapped therapeutic target for cancer and other proliferative diseases2.
In their paper published in the 26 September 2017 issue of Cell Reports, Kwon et al. (Yao) describe a bistable mechanism that correlates with depth of quiescence which they termed the Rb--E2F Switch2. E2F is a transcription factor that binds to E2F responsive elements in a set of target genes that drive entry and progression through the cell cycle3. Rb is a tumor suppressor and transcription factor that regulates proliferation in essentially all cell types4. Rb suppresses cell cycle progression by inhibiting the action of E2F1,2,4. A spectrum of growth and inhibitory signals is converted to a binary OFF/ON signal by E2F, resulting in either quiescence or proliferation2,4. Rb plays a key role in setting the threshold for E2F activation.
The E2F OFF/ON threshold determines the depth of quiescence of a given cell2. The E2F threshold is essentially the strength of the growth signal(s) required for a cell to exit quiescence and re-enter the cell cycle. Many factors play a role in setting the E2F threshold2,4. During quiescence Rb binds to E2F preventing it from activating cell cycle progression1. Myc, Cyclin D/CDK4,6 and Cyclin E/CDK2 lower the E2F threshold by phosphorylating Rb, preventing it from binding E2F1,2,4. CDK Inhibitors (e.g. p21, 16, p27) raise the E2F threshold by blocking phosphorylation of Rb, allowing it to bind E2F and suppress cell cycle progression1,2,4. Thus, the E2F OFF/ON threshold is a balance between the positive and negative influencers of E2F activation within each cell. The deeper the quiescence, the stronger and longer the growth signal must be to "revive" the cells2. E2F OFF-to-ON switching correlated with exit from either deep or shallow quiescence2. Deep quiescent cells have a higher E2F switching threshold as fewer deep quiescence cells were able to switch on E2F under the same growth conditions as cells in shallow quiescence. Deep quiescent cells also exhibited delayed E2F activation and DNA replication compared to cells in shallow quiescence2.
Cells may enter a state of quiescence to protect themselves from a hostile environment. In the case of tumor cells, quiescence may allow them to escape the toxic effects of chemotherapeutic agents. Driving them back into the cell cycle may restore their susceptibility to cytotoxic drugs. The ability to manipulate the transition between quiescence and proliferation pharmacologically may further allow us to regulate the proliferation and differentiation of stem cells, and control proliferation of immune cells involved in autoimmunity, inflammation, and transplant rejection.
1. Arand J, and Sage J. 2017. G1 cyclins protect pluripotency. Nat Cell Biol. Mar 1;19(3):149-150.
2. Kwon JS, Everetts NJ, Wang X, Wang W, Della Croce K, Xing J, Yao G. 2017. Controlling depth of cellular quiescence by an Rb-E2F network switch. Cell Rep. Sept 26;20(13):3223-3235.
3. Poppy Roworth A, Ghari F, La Thangue NB. 2015. To live or let die - complexity within the E2F1 pathway. Mol Cell Oncol. Jan 30;2(1):e970480.
4. Yao G1. 2014. Modelling mammalian cellular quiescence. Interface Focus. June 6;4(3): 20130074.