Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity

Ginzberg, Miriam Bracha; Chang, Nancy; D'Souza, Heather; Patel, Nish; Kafri, Ran; Kirschner, Marc W.

doi:10.7554/elife.26957

Cited by 104 publications

(175 citation statements)

References 49 publications

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“…The Rb‐E2F switch is also influenced by cell size and other metabolic measures of a cell’s readiness to divide. Although the precise mechanism through which cell size regulates G1 progression in mammalian cells remains unclear , an inhibitor‐dilution mechanism has recently been proposed to control cell cycle re‐entry in yeast . During G1, expression of the yeast G1 cyclin Cln3 scales proportionally with cell size, while the expression of Whi5, a transcriptional inhibitor of cell cycle progression, remains constant.…”

Section: Factors Influencing the Rb‐e2f Bistable Switchmentioning

confidence: 99%

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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Section: Factors Influencing the Rb‐e2f Bistable Switchmentioning

confidence: 99%

Bistable switches as integrators and actuators during cell cycle progression

et al. 2019

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“…RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rbdilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.Phenomenologically, cell size control is achieved through size-dependent changes in cell growth rate or cell cycle progression 5,6,13,14 . Size-dependent changes in cell growth rate can control size when larger cells grow slower than cells nearer the target size, which may be due to an observed optimum cell size for mitochondrial potential 15 .…”

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confidence: 99%

Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

Zatulovskiy

Berenson

Topacio

2018

Preprint

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J.M.S.) Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport 1,2 . Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division 3-6 . While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive 7-12 . Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. RB is transcriptionally regulated so that Rb protein is synthesized mostly during S and G2 phases, and remains stable throughout the cell cycle. The amount of Rb synthesized and partitioned to daughter cells is independent of cell size, ensuring all cells at birth inherit a similar sizeindependent amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rbdilution by cell growth in G1 provides a cell autonomous molecular mechanism for cell size homeostasis.Phenomenologically, cell size control is achieved through size-dependent changes in cell growth rate or cell cycle progression 5,6,13,14 . Size-dependent changes in cell growth rate can RB at its endogenous locus with two green fluorescent proteins and a triple FLAG epitope tag ( Fig. 1c-d). We tagged RB in HMEC-hTERT1 cells, a non-transformed human epithelial cell line previously used to identify mutations affecting cell proliferation 26 . We imaged and tracked asynchronously cycling RB-3xFLAG-Clover-sfGFP cells over multiple days using an automated widefield microscope (Fig. 1e, Extended data Fig. 1a-c, Supplementary data Movie 1).Consistent with the Rb-dilution model, the amount of Rb was constant for the first 5-10 hours after mitosis, which corresponded to the G1 phase as measured using a FUCCI cell cycle reporter 27 . Rb amount then increased during S/G2/M cell cycle phases ( Fig. 1f-h, Extended data Fig. 1c). Meanwhile, the nuclear volume, within which Rb is distributed, increased steadily through the cell cycle (Fig. 1i). To further confirm that HMEC cells grow and accumulate protein

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“…This way, all cells reach a similar size at division. However, adders, where cells grow a constant amount over a single cycle independent of birth size, more closely approximate the size control exhibited by a variety of animal cell lines grown in vitro [9,10,27,32]. Here, in contrast to expectations from in vitro studies, we show that mouse epidermal stem cells exhibit an overall sizer in vivo, and variation in cell birth size is compensated for within one cell cycle.…”

Section: Discussionmentioning

confidence: 48%

“…Rather, larger cells are growing faster than smaller cells, and this relationship between size and growth rate is similar in G1 and S/G2/M cells. However, higher temporal resolution is required to more precisely determine the cell growth function and its relationship to exponential growth (where the cell growth rate is directly proportional to cell size), which has implications for cell size control [9,21,22,37].…”

Section: Discussionmentioning

confidence: 99%

A G1 sizer mechanism coordinates growth and division in the mouse epidermis

Xie

2019

Preprint

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Cell size homeostasis is often achieved by coupling cell cycle progression to cell growth. Studies of cell size homeostasis in single-celled bacteria and yeast have observed several distinct phenomena. Growth can be coupled to division through a range of mechanisms, including a 'sizer', wherein cells of varying birth size divide at similar final sizes [1-3], and an 'adder', wherein cells increase in size a fixed amount per cell cycle [4][5][6]. Importantly, intermediate control mechanisms are observed, and even the same organism can exhibit distinct control phenomena depending on growth conditions [2,7,8]. While studying unicellular organisms in laboratory conditions may give insight into their growth control in the wild, this is less apparent for studies of mammalian cells growing outside the organism. Sizer, adder, and intermediate mechanisms have been observed in vitro [9-12], but it is unclear how these diverse size homeostasis phenomena relate to mammalian cell proliferation in vivo. To address this gap, we analyzed time-lapse images of the mouse epidermis taken over one week during normal tissue turnover [13]. We quantified the 3D volume growth and cell cycle progression of single cells within the mouse skin. In dividing epidermal stem cells, we found that cell growth is coupled to division through a sizer mechanism operating largely in the G1 phase. Thus, while the majority of tissue culture studies to-date identified adder mechanisms, our analysis demonstrates that sizer mechanisms are important in vivo and highlights the need to determine their underlying molecular origin.

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Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity

Cited by 104 publications

References 49 publications

Bistable switches as integrators and actuators during cell cycle progression

Bistable switches as integrators and actuators during cell cycle progression

Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

A G1 sizer mechanism coordinates growth and division in the mouse epidermis

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