Understanding mammalian cell size control
This analysis explains how cell size is maintained through a combination of interdivision time variation and cell growth rate variation. Exponential growth is possible and allowed during the division cycle, in contrast to the proposal of Conlon and Raff [1
]. The ideas presented here are a fresh way to look at the cell cycle and cell growth in eukaryotic cells, even though the ideas have been around for over three decades due to work on size determination in bacteria (Cooper, 1979; Helmstetter, 1969). The model of the cell cycle presented here explains many experimental results without postulating checkpoints, G1-phase events, restriction points, or similar phenomena. Experimental support for these ideas [28
] and the application of these ideas to other problems of cell growth and differentiation [3
] have been published. These ideas have also been reviewed [36
It may be best to summarize these two contrasting views of size maintenance by looking at cell growth in a simple manner, and asking how the rate of mass increase is related to the passage of the cell through the cell cycle. The model of Conlon and Raff looks at the events of passage through the cell cycle as occurring independently of mass increase. The problem then remains as to how mass increase fits into, or coordinates with, the pattern or timing of passage through the cell cycle. It is as though the cell moves through the cell cycle without considering the mass problem, and then the mass of the cell looks at the cell cycle and says "I must grow at some rate so that I do not get too big or too small." In the Conlon/Raff model, a control exists that coordinates mass increase with the rate of cell division.
The model presented here–in contrast to the model of Conlon and Raff–situates mass as the driving force of the cell cycle. Mass increases at some rate that is determined by external conditions (medium, growth factors, pH, etc.). As the mass increases, the accumulation of mass starts or regulates passage through the cell cycle. A cell cannot grow to an abnormal larger size because at a certain cell size or cell mass the S phase is initiated and this event starts a sequence of events leading to mitosis and cytokinesis. A cell cannot get too small because if mass grows slowly (or even stops growing) then the later events of the cell cycle (S-, G2-, and M-phases) are delayed (or do not occur) until mass increases sufficiently to start S phase. A cell cannot get too large because at a certain size the cell initiates S phase leading to the relatively early cell division. A cell cannot get too small because if mass accumulation is inhibited then S phase initiations are also inhibited.
Thus, there is no problem relating mass increase and the cell cycle. Cell mass growth and cell cycle passage cannot be dissociated because one (mass increase) is the determinant of the other (S-phase initiation). For this reason one needs neither checkpoints nor control elements outside of mass increase.
The time for mass to double in a particular situation determines the doubling time of a culture. This is because initiations of S phase occur every mass doubling time, and cell divisions similarly occur every mass doubling time. Thus total mass increases at the same rate as total cell number.
The model presented here explains size determination, size maintenance, and the relationship of mass increase and cell number increase in a growing, exponential, unperturbed, mammalian cell cultures.
This paper is dedicated to Moselio Schaechter, who has supported and encouraged me over the years, who was a participant in what has been called "the Fundamental Experiment of Bacterial Physiology", the experiment that is the basis for the eukaryotic ideas presented here, and who has been a model scientist, person, and mentor.
Additional material on the ideas presented here may be viewed at http://www.umich.edu/~cooper.
I thank Charles Helmstetter, Robert Brooks, Arthur Koch, Martin Raff, Ian Conlon, and Sanjav Grewal for their comments and suggestions. Further comments, thoughts, critiques, suggestions, or ideas from readers of this article are most welcome