A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells

Heldt, Stefan; Barr, Alexis R.; Cooper, Sam; Bakal, Chris; Novák, Béla

doi:10.1073/pnas.1715345115

Cited by 78 publications

(105 citation statements)

References 43 publications

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“…Various computational models have been developed to integrate these mechanisms into a quantitative framework. These models have provided invaluable insights into the cell cycle's temporal organization (Orlando et al , ; Tyson & Novak, ), adaptation to stress (Heldt et al , ), role in cellular decision making (Spencer et al , ; Dong et al , ; Cappell et al , ), and irreversible nature (Novak et al , ). However, these models do not account for the observed distribution of cell cycle phase durations in single cells nor do they explain how phase durations can be both heritable and independent.…”

Section: Discussionmentioning

confidence: 99%

Evidence that the human cell cycle is a series of uncoupled, memoryless phases

Chao

Fakhreddin

Shimerov

et al. 2019

Molecular Systems Biology

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The cell cycle is canonically described as a series of four consecutive phases: G1, S, G2, and M. In single cells, the duration of each phase varies, but the quantitative laws that govern phase durations are not well understood. Using time‐lapse microscopy, we found that each phase duration follows an Erlang distribution and is statistically independent from other phases. We challenged this observation by perturbing phase durations through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Despite large changes in durations in cell populations, phase durations remained uncoupled in individual cells. These results suggested that the independence of phase durations may arise from a large number of molecular factors that each exerts a minor influence on the rate of cell cycle progression. We tested this model by experimentally forcing phase coupling through inhibition of cyclin‐dependent kinase 2 ( CDK 2) or overexpression of cyclin D. Our work provides an explanation for the historical observation that phase durations are both inherited and independent and suggests how cell cycle progression may be altered in disease states.

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Section: Discussionmentioning

confidence: 99%

Evidence that the human cell cycle is a series of uncoupled, memoryless phases

Chao

Fakhreddin

Shimerov

et al. 2019

Molecular Systems Biology

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“…After the switch to a high E2F steady state, elevated CDK2 activity is sufficient to keep Rb hyperphosphorylated and the system remains in the high E2F steady state even if mitogenic stimuli are completely removed. In this way, the Rb‐E2F switch is irreversible with respect to mitogenic stimulation under normal physiological conditions (Fig. B).…”

Section: Factors Influencing the Rb‐e2f Bistable Switchmentioning

confidence: 95%

Bistable switches as integrators and actuators during cell cycle progression

et al. 2019

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Progression through the cell cycle is driven by bistable switches—specialized molecular circuits that govern transitions from one cellular state to another. Although the mechanics of bistable switches are relatively well understood, it is less clear how cells integrate multiple sources of molecular information to engage these switches. Here, we describe how bistable switches act as hubs of information processing and examine how variability, competition, and inheritance of molecular signals determine the timing of the Rb‐E2F bistable switch that controls cell cycle entry. Bistable switches confer both robustness and plasticity to cell cycle progression, ensuring that cell cycle events are performed completely and in the correct order, while still allowing flexibility to cope with ongoing stress and changing environmental conditions.

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“…We propose that, identical to normal cells, the proliferation-quiescence decision in BRAFV600E melanoma cells is still dependent on the mitogenic/pro-proliferative cues via MEK-ERK (23,24,67,68). Whilst the presences of the BRAFV600E mutation largely circumvents the need for exogenous mitogen in melanoma cells, it is insufficient to override the actions of CDK inhibitors (CKIs) such as p21CIP1/WAF1 that can be upregulated following events such an endogenous DNA damage (56,67,68). Upregulation of CKIs, and/or downregulation of CDK activity engages mechanisms that then down-regulate ERK activity ( Figure 9).…”

Section: Discussionmentioning

confidence: 97%

“…While the basis for cell-to-cell differences in ERK activity in BRAFV600E cells remains unclear, our data suggests the mechanisms, which promote and/or antagonize BRAF-MEK-ERK activity to generate these differences are controlled in cell-cycle dependent fashions. We propose that, identical to normal cells, the proliferation-quiescence decision in BRAFV600E melanoma cells is still dependent on the mitogenic/pro-proliferative cues via MEK-ERK (23,24,67,68). Whilst the presences of the BRAFV600E mutation largely circumvents the need for exogenous mitogen in melanoma cells, it is insufficient to override the actions of CDK inhibitors (CKIs) such as p21CIP1/WAF1 that can be upregulated following events such an endogenous DNA damage (56,67,68).…”

Section: Discussionmentioning

confidence: 99%

“…In normal cells, mitogenic signaling converges on CDK2 activity, which together with the extent of DNA damage determines the outcome of the proliferation-quiescence decision (23,24,56,67,68). We thus sought to determine the role of BRAF-MEK-ERK signaling in the regulation of CDK2 activity following BRAF or MEK inhibition; by monitoring CDK2 activity using a reporter we have developed (66).…”

Section: Passage Through the Restriction Point Initiates A Positive Fmentioning

confidence: 99%

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The dynamics of ERK signaling in melanoma, and the response to BRAF or MEK inhibition, are cell cycle dependent

Simpson

Bakal

2018

Preprint

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Activating BRAF mutations are thought to drive melanoma tumorigenesis and metastasis by constitutively activating MEK and ERK. Small molecule inhibitors (SMIs) of BRAF or MEK have shown promise as melanoma therapeutics. However, the development of resistance to these inhibitors in both the short-and long-term is common; warranting investigation into how these SMIs influence ERK signaling dynamics. Quantitative single cell imaging of ERK activity in living cells reveals both intra-and inter-cell heterogeneity in this activity in isogenic melanoma populations harboring a BRAFV600E mutation. This heterogeneity is largely due to a cell-cycle dependent bifurcation of ERK activity.Moreover, we show there are also cell-cycle dependent responses in ERK activity following BRAF or MEK inhibition. Prior to, but not following, CDK4/6-mediated passage through the Restriction Point (RP) ERK activity is sensitive to BRAF and MEK inhibitors. In contrast, for cells that have passed the RP, ERK activity will remain elevated in the presence of BRAF or MEK inhibition until mitosis. Our results show that ERK activityeven in the presence of activating BRAF mutations -is regulated by both positive and negative feedback loops that are engaged in cell-cycle dependent fashions. CDK4/6 inhibition sensitizes ERK activity to BRAF or MEK inhibition by preventing passage the transition from a BRAF/MEK dependent to independent state. Our results have implications for the use of MEK and BRAF inhibitors as melanoma therapeutics, and offer a rational basis for the use of these inhibitors in combination with CDK4/6 inhibition during cancer therapy.

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A comprehensive model for the proliferation–quiescence decision in response to endogenous DNA damage in human cells

Cited by 78 publications

References 43 publications

Evidence that the human cell cycle is a series of uncoupled, memoryless phases

Evidence that the human cell cycle is a series of uncoupled, memoryless phases

Bistable switches as integrators and actuators during cell cycle progression

The dynamics of ERK signaling in melanoma, and the response to BRAF or MEK inhibition, are cell cycle dependent

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