Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Cell Biol. Author manuscript; available in PMC 2011 December 1.
Published in final edited form as:
PMCID: PMC2988085

Growth and Division – not a one-way road


Maintaining cell size homeostasis and regulating cell size in response to changing conditions is a fundamental property of organisms. Here we examine the recent advances in our understanding of the interplay between accumulation of mass (growth) and the progression through the cell cycle (proliferation), the coordination of which determines the size of cells. It is well established that growth affects cell division (reviewed in [1]). This review will focus on the reverse, less well-defined relationship – how cell cycle progression affects growth. We will summarize findings that indicate that growth is not constant during the cell cycle and discuss the surprising possibility that cyclin-dependent kinases (CDKs) inhibit growth.


All organisms, from single celled bacteria and yeast, to multi-cellular organisms can vary and adjust the size of their cells, to optimize growth, storage, regenerative capacity, or production capacity [2]. It is well established that cells need to reach a critical size in order to initiate a new cell cycle, although there are specific exceptions in multicellular organisms (reviewed in [1,3]. If growth is inhibited by starvation or by chemical inhibitors of macromolecular synthesis, cells stop proliferating. In the presence of nutrients or appropriate intracellular cues, cell growth is stimulated by the activity of the Tor and RAS pathways, and cells division can occur (reviewed in [46]. The regulation of proliferation by growth has been extensively covered recently and we wish to direct the readers to the following excellent reviews and books on this topic [1,2,4,79]. This review will focus on recent advances in understanding how cell cycle transitions affect growth in eukaryotes and discuss the importance of this regulation.

Growth rate changes at multiple points during the cell cycle of Schizosaccharomyces pombe

The rod-shaped yeast Schizosaccharomyces pombe grows by elongation at the cell poles (Figure 1A). Microscopic size measurements of S. pombe cells showed that the growth rate changes during the cell cycle. These points of change are called the Rate Change Points (RCPs) [10,11]. After cell division each daughter cell is half the size of the mother and should therefore grow at half the rate of the mother cell. This is not the case. The newly born daughter cells grow faster than half the rate of the mother cell. This change in growth rate that coincides with cell division is called RCP1 (Figure 1B) [12]. In the newborn cells, growth occurs only from the old pole of the cell (Figure 1A). This early growth rate depends on nutrient conditions and strain background [11]. During mid-G2, growth rate increases again by approximately 30% (RCP2; Figure 1B). This change in growth rate coincides with the switch from mono-polar growth (growth only at the old pole) to bi-polar growth (growth at both poles) [10,13], a transition that has been termed NETO (New-End-Take-Off). Curiously however, RCP2 does not depend on NETO. wee1 and cdc11 conditional mutants, in which NETO does not take place, show a growth rate increase at RCP2 [10,11]. Instead, RCP2 depends on the completion of DNA replication. When DNA replication is inhibited with hydroxyurea, RCP2 is not detected [14**]. The degree of increase in growth at RCP2 is sensitive to growth conditions and genotype. Furthermore, RCP2 is under size control [11]. The timing of RCP2 is inversely correlated to the birth size of the cell [11]. During mitosis, most likely during early anaphase, growth rate changes again. This growth rate change does not have a name (shown as an asterisk in Figure 1B) but is the starting point of what is known as the constant size period [10,12].

Figure 1
Growth during the cell cycle in S. pombe

Measurement of protein and RNA synthesis in synchronously growing S. pombe cells confirmed growth rate changes during the cell cycle [15,16]. At 25°C, the amount of S35 labeled protein increases during the first 75% of the cell cycle, but then remains constant during the last 25% of the cell cycle [15] (Figure 1B). Protein synthesis then increased again at the “acceleration point”, which coincides with or slightly precedes RCP1 at the beginning of the next cell cycle (reviewed in [12]). At 17°C, protein synthesis markedly decreases during the constant length period, more closely mimicking the growth pattern of cells [17].

Although it is clear that growth rate is under cell cycle control in S. pombe the molecular mechanisms that modulate growth in response to cell cycle cues remain to be elucidated. Cyclin-dependent kinases (CDKs) appear to be required – directly or indirectly - for the slowing of growth rate during mitosis. Cells carrying temperature sensitive mutations in the sole fission yeast CDK, cdc2+, arrest in G2 and the drastic reduction in growth that occurs during mitosis, does not take place [10]. The regulation of RCP1 is likely related to the cell cycle events that occur at the end of mitosis. Septum formation, however does not appear to be one of these events, as cdc11 mutants, which are incapable of forming a septum, still exhibit both RCP1 and RCP2 [10], at least during the first cell cycle after inhibition of cdc11+ function.

Ploidy is a key determinant of growth rate. Cells with a higher DNA content grow faster than cells with a lower one (reviewed in [1]). It is tempting to speculate that RCP2 reflects, at least in part, the increase in ploidy that has occurred by G2. It is also worth noting that changes in growth rate during the cell cycle also implies that the growth pattern of S. pombe cells does not conform to either a simple exponential or single linear model [12,14**].

Actin polarization limits cell growth in budding yeast

Several studies of the growth of the budding yeast Saccharomyces cerevisiae indicate that growth is constant throughout the cell cycle. Protein synthesis does not appear to vary during the cell cycle [18]. Measurement of a protein synthesis reporter in single cells or measurement of growth by estimating cell volumes by microscopy of synchronized cultures supported this conclusion [19,20]. Other studies reported growth rate changes during the cell cycle [21,22]. By examining dry cell mass by interference microscopy, Murdock Mitchison reported a growth rate of 0.17pg/min during G1, followed by a double growth rate of 0.32pg/min after budding (Figure 2A, solid line). When measuring growth by volume using light microscopy for the same cells, Mitchison observed a slightly different pattern: cells grew at a given rate until before budding, then growth slowed down, then it increased at a faster rate (Figure 2A, dashed line). A recent examination of the growth rates of S. cerevisiae cell division cycle (cdc) mutants that arrest at different points of the cell cycle cells using volume displacement (coulter counter) support this idea of varying growth rates during the cell cycle. Cells arrested at different cell cycle stages grow at different rates and the maximal cell size reached in the arrest varies greatly between cell cycle stages (Figure 2B). Cells arrested in G1 by the inactivation of the single CDK in budding yeast, Cdc28, grow the most [23**]. High growth rates were also observed in anaphase-arrested cells. Cells that arrest at the time of cell cycle entry or in metaphase exhibited lower growth rates. Microscopic measurements of wild type single cells also suggested a slowing of growth at the time of budding, indicating that at least some of the differences in growth rate observed in cell cycle arrests are not artifacts of the cell cycle arrests [23**].

Figure 2
Growth during the cell cycle in S. cerevisiae

One mechanism whereby cell cycle events affect growth is through changes in the actin cytoskeleton. In order to grow in size, cells must fuse new lipid vesicles with the cell membrane. The vesicles are transported to sites of fusion on actin cables by Myosin V [2426]. The actin cytoskeleton undergoes dramatic changes during the cell cycle (Figure 2C). In G1 phase, actin cables are evenly distributed throughout the cytoplasm, resulting in uniform vesicle deposition, isotropic growth and spherical cell morphology (Figure 2Ci). As cells enter the cell cycle, the actin cytoskeleton becomes polarized through the action of the Cln cyclin G1 CDKs (Figure 2Cii) and vesicle deposition occurs apically at the site of bud emergence (Figure 2Ciii). After initial bud emergence, growth remains limited to the developing daughter cell, but becomes isotropic to create a spherical bud (Figure 2Civ) [2426].

Studies of cdc mutants and of cells treated with the mating pheromone α-factor, which polarizes the actin cytoskeleton and causes mating projection formation, showed that polarization of the actin cytoskeleton decreases growth. Mutants that arrest with high G1-CDK activity (cdc34 or cdc53 mutants) or form mating projection showed decreased growth and protein synthesis rates compared to other cell cycle arrests. Preventing actin polarization after pheromone treatment suppressed the growth inhibitory effects of pheromone [23**]. Inactivation of actin organizers or inactivation of cyclin-CDK activity also improved the growth of cells that arrest with a hyper-polarized actin cytoskeleton such as cdc34 mutants [23**].

The actin cytoskeleton not only affects growth but also appears to influence cellular density. Murdock Mitchison predicted that cell density peaks around the time of budding [21]. Several studies provided experimental proof for this prediction [21, 2729]. How do changes in the actin cytoskeleton affect cell growth and density and are these two events connected? A simple hypothesis is that at the time of budding, the cell surface increases at a lower rate but initially protein synthesis continues at the same rate. This results in a temporary (<30min) uncoupling of cell surface growth and protein synthesis and hence increased cell density. The basis for this observation could be the properties of apical growth: there is limited space at the bud tip and only few vesicles are incorporated into the membrane to contribute to cell surface growth (Figure 2C). Initially protein synthesis continues unabated causing a transient increase in cell density. Sometimes thereafter feedback mechanisms are activated that down-regulate protein synthesis in response to actin hyperpolarization.

How actin polarization leads to the down-regulation of protein synthesis is not understood, but the analysis of mutants defective in secretion could provide a framework for how to think about this signaling mechanism. In cells defective for secretion, unincorporated vesicles accumulate [30]. Secretion mutants also show decreased protein synthesis rates [31]. The cell wall integrity (Pkc1) pathway, which senses cell wall stress [32], down-regulates protein synthesis in these secretion mutants [33,34]. Polarized growth may create a similar situation as is observed in secretion mutants. The area of membrane where vesicles can be deposited is limited (Figure 2Cii and iii), which may lead to the accumulation of unincorporated vesicles. This could cause activation of the Pkc1 pathway and hence a down-regulation of protein synthesis.

Other cell cycle events could also regulate growth in budding yeast. Cells arrested in metaphase, grow relatively little compared to G1 arrested cells, although the actin cytoskeleton is not highly polarized in this arrest. Regulators of anaphase entry, i.e. the ubiquitin ligase APC, could accelerate growth as cells exit from mitosis and resume rapid growth. Like in S. pombe, duplication of the DNA content could also accelerate growth. However, given the poorly defined nature of G2 in S. cerevisiae, detecting this growth rate change may be difficult.

Cell cycle regulated growth in mammalian cells

Growth properties during the cell cycle have also been examined in mammalian cells. These studies demonstrated that RNA and protein synthesis varies during the cell cycle, with a sharp decrease in both taking place during mitosis [35]. The transcriptional down-regulation is thought to be due to chromosome condensation [36], the decrease in translation is due to the switch from cap-dependent to cap independent translation [37]. This change is mediated by inhibiting components of cap dependent initiation of translation, eIF4E and eIF4B [37,38**]. Interestingly, if this translation switch is abolished, cells undergo an aberrant mitosis. Cytokinesis is impaired leading to the formation of bi-nucleate or incompletely separated cells, which is suppressed by reducing protein synthesis through treatment with the TOR inhibitor rapamycin [38**]. The regulation of the mitotic translation is often lost in tumor cells, indicating that the coordination of growth with cell cycle phase has important implications for disease development [38**].

Recent studies of single celled mouse lymphoblast revealed additional regulation of growth by the cell cycle. Attaching cells to a membrane and capturing the cells that bud of the captured ones can be used to synchronize the lymphoblasts. This “baby-machine” allows for the isolation of new-born G1 cells whose growth properties can be analyzed as they progress through the cell cycle in a synchronous manner [39**]. Although the growth characteristics of single lymphoblasts may be different from cells that exist in tissues, the studies revealed that the co-ordination of cell growth with division is remarkably similar in mammalian cells as in single-celled organisms. Growth is proportional to cell size and cells need to reach a critical size before they can divide. Most striking was the discovery that, as in budding yeast, cells increase their growth rates the fastest in G1 compared to other stages of the cell cycle [39**]. A decrease in growth rate at the end of the cell cycle was also observed (cells larger than 2000 fL), consistent with the observation that mammalian cells dramatically decrease protein synthesis during mitosis. The molecular mechanisms accelerating growth during G1 and whether CDKs are involved in this regulation remains to be determined.

Conclusions and outlook

Maintaining the proper growth rate at the proper stage of the cell cycle (“balanced growth” [12]) is a fundamental property of cells that needs to be regulated in order to maintain a constant cell size. Observations from various model systems indicate that progression through the cell cycle affects growth rate. Furthermore it appears that growth is maximal during the major GAP phase of an organism - G1 in budding yeast and mammalian cells and G2 in S. pombe. Why would cells separate the maximal growth phase from the division phase? Cells may have evolved this mechanism in order to build up the necessary cellular resources prior to the increased energy demands of DNA replication and chromosome segregation. This notion of resource accumulation is consistent with the concept of cell cycle commitment, called Start in yeast and the Restriction Point in mammalian cells [40,41]. Once cell cycle entry has occurred, CDK mediated events may help ensure that less energy is directed to protein synthesis and hence available for duplication and segregation of the genetic material. Furthermore, in terminally differentiated tissues a high G1 growth potential may aid in the regeneration of tissue in the absence of cell division [42]. The molecular mechanisms enhancing growth during G1 or that down-regulate it in the other cell cycle stages remain to be elucidated, but it would not be surprising if CDKs are central to this regulation. CDKs could regulate growth indirectly – by modulating actin cytoskeleton polarity – and/or affect macromolecule synthesis directly by modulating the activity of the biosynthetic machinery. Indeed, studies in several organisms indicate that, as in S. cerevisiae and S. pombe, cells lacking CDK function grow large [43,44], however a careful comparison of the growth rates of CDK deficient cell and other types of arrests has not yet been performed in these organisms.

The next five years will likely see great advances in understanding how growth and division interact and regulate each other. New powerful methods for measuring growth and mass at the single cell level such as the SMR (Suspended Microchannel Resonator) technique, will contribute to our understanding of the regulation of cell growth. SMR measures the buoyant mass of a particle (cells) and has already been used successfully to measure the mass and density of different cell types and growth rates of single eukaryotic and prokaryotic cells for short (<5min) or longer (>20min) times [27,45,46**]. The SMR will be the ideal tool to carefully dissect when growth rate changes occur during the cell cycle and to begin to describe the framework within which this regulation operates.


This work is supported by 1-U54-CA143874-01 NIH grant to AA and American Cancer Society Fellowship to AG. A.A is also an investigator of the Howard Hughes Medical Institute. We thank members of the Amon lab for useful comments and suggestions regarding the manuscript.


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References and Recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

* of special interest

** of outstanding interest

1. Jorgensen P, Tyers M. How cells coordinate growth and division. Curr Biol. 2004;14:R1014–1027. [PubMed]
2. Hall MN, Raff M, Thomas G. Cell Growth: Control of Cell Size. Cold Spring Harbor Laboratory Press; 2004.
3. Conlon IJ, Dunn GA, Mudge AW, Raff MC. Extracellular control of cell size. Nat Cell Biol. 2001;3:918–921. [PubMed]
4. Zaman S, Lippman SI, Zhao X, Broach JR. How Saccharomyces responds to nutrients. Annu Rev Genet. 2008;42:27–81. [PubMed]
5. Inoki K, Ouyang H, Li Y, Guan KL. Signaling by target of rapamycin proteins in cell growth control. Microbiol Mol Biol Rev. 2005;69:79–100. [PMC free article] [PubMed]
6. Sarbassov DD, Ali SM, Sabatini DM. Growing roles for the mTOR pathway. Curr Opin Cell Biol. 2005;17:596–603. [PubMed]
7. Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, Tyers M. A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev. 2004;18:2491–2505. [PubMed]
8. Saucedo LJ, Edgar BA. Why size matters: altering cell size. Curr Opin Genet Dev. 2002;12:565–571. [PubMed]
9. Su TT, O’Farrell PH. Size control: cell proliferation does not equal growth. Curr Biol. 1998;8:R687–689. [PMC free article] [PubMed]
10. Mitchison JM, Nurse P. Growth in cell length in the fission yeast Schizosaccharomyces pombe. J Cell Sci. 1985;75:357–376. [PubMed]
11. Sveiczer A, Novak B, Mitchison JM. The size control of fission yeast revisited. J Cell Sci. 1996;109 (Pt 12):2947–2957. [PubMed]
12. Mitchison JM. Growth during the cell cycle. Int Rev Cytol. 2003;226:165–258. [PubMed]
13. Streiblova E, Wolf A. Cell wall growth during the cell cycle of Schizosaccharomyces pombe. Z Allg Mikrobiol. 1972;12:673–684. [PubMed]
**14. Baumgartner S, Tolic-Norrelykke IM. Growth pattern of single fission yeast cells is bilinear and depends on temperature and DNA synthesis. Biophys J. 2009;96:4336–4347. This manuscript shows that the change in growth rate during G2 depends on DNA replication. [PubMed]
15. Creanor J, Mitchison JM. Patterns of protein synthesis during the cell cycle of the fission yeast Schizosaccharomyces pombe. J Cell Sci. 1982;58:263–285. [PubMed]
16. Elliott SG. Coordination of growth with cell division: regulation of synthesis of RNA during the cell cycle of the fission yeast Schizosaccharomyces pombe. Mol Gen Genet. 1983;192:204–211. [PubMed]
17. Mitchison JM, Wilbur KM. The incorporation of protein and carbohydrate precursors during the cell cycle of a fission yeast. Exp Cell Res. 1962;26:144–157. [PubMed]
18. Elliott SG, McLaughlin CS. Rate of macromolecular synthesis through the cell cycle of the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1978;75:4384–4388. [PubMed]
19. Di Talia S, Skotheim JM, Bean JM, Siggia ED, Cross FR. The effects of molecular noise and size control on variability in the budding yeast cell cycle. Nature. 2007;448:947–951. [PubMed]
20. Woldringh CL, Huls PG, Vischer NO. Volume growth of daughter and parent cells during the cell cycle of Saccharomyces cerevisiae a/alpha as determined by image cytometry. J Bacteriol. 1993;175:3174–3181. [PMC free article] [PubMed]
21. Mitchison JM. The growth of single cells. II Saccharomyces cerevisiae. Exp Cell Res. 1958;15:214–221. [PubMed]
22. Bayne-Jones S, Adolph EF. Growth in size of micro-organisms measured from motion pictures I. Yeast, saccharomyces cerevisiae. J Cellular Comp Physiol. 1932;1:387–407.
**23. Goranov AI, Cook M, Ricicova M, Ben-Ari G, Gonzalez C, Hansen C, Tyers M, Amon A. The rate of cell growth is governed by cell cycle stage. Genes Dev. 2009;23:1408–1422. This paper shows that growth rates vary between different cell cycle arrests. Growth rate also appears to change in single cells during an unperturbed cell cycle. The manuscript also shows that actin polarization inhibits growth. [PubMed]
24. Pruyne D, Legesse-Miller A, Gao L, Dong Y, Bretscher A. Mechanisms of polarized growth and organelle segregation in yeast. Annu Rev Cell Dev Biol. 2004;20:559–591. [PubMed]
25. Moseley JB, Goode BL. The yeast actin cytoskeleton: from cellular function to biochemical mechanism. Microbiol Mol Biol Rev. 2006;70:605–645. [PMC free article] [PubMed]
26. Park HO, Bi E. Central roles of small GTPases in the development of cell polarity in yeast and beyond. Microbiol Mol Biol Rev. 2007;71:48–96. [PMC free article] [PubMed]
27. Bryan AK, Goranov A, Amon A, Manalis SR. Measurement of mass, density, and volume during the cell cycle of yeast. Proc Natl Acad Sci U S A. 2009 [PubMed]
28. Hartwell LH. Periodic Density Fluctuation During the Yeast Cell Cycle and the Selection of Synchronous Cultures. J Bacteriol. 1970;104:1280–1285. [PMC free article] [PubMed]
29. Baldwin WW, Kubitschek HE. Buoyant density variation during the cell cycle of Saccharomyces cerevisiae. J Bacteriol. 1984;158:701–704. [PMC free article] [PubMed]
30. Lew DJ, Simon SM. Characterization of constitutive exocytosis in the yeast Saccharomyces cerevisiae. J Membr Biol. 1991;123:261–268. [PubMed]
31. Mizuta K, Warner JR. Continued functioning of the secretory pathway is essential for ribosome synthesis. Mol Cell Biol. 1994;14:2493–2502. [PMC free article] [PubMed]
32. Levin DE. Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2005;69:262–291. [PMC free article] [PubMed]
33. Nierras CR, Warner JR. Protein kinase C enables the regulatory circuit that connects membrane synthesis to ribosome synthesis in Saccharomyces cerevisiae. J Biol Chem. 1999;274:13235–13241. [PubMed]
34. Li Y, Moir RD, Sethy-Coraci IK, Warner JR, Willis IM. Repression of ribosome and tRNA synthesis in secretion-defective cells is signaled by a novel branch of the cell integrity pathway. Mol Cell Biol. 2000;20:3843–3851. [PMC free article] [PubMed]
35. Prescott DM, Bender MA. Synthesis of RNA and protein during mitosis in mammalian tissue culture cells. Exp Cell Res. 1962;26:260–268. [PubMed]
36. King DW, Barnhisel ML. Synthesis of RNA in mammalian cells during mitosis and interphase. J Cell Biol. 1967;33:265–272. [PMC free article] [PubMed]
37. Pyronnet S, Dostie J, Sonenberg N. Suppression of cap-dependent translation in mitosis. Genes Dev. 2001;15:2083–2093. [PubMed]
**38. Wilker EW, van Vugt MA, Artim SA, Huang PH, Petersen CP, Reinhardt HC, Feng Y, Sharp PA, Sonenberg N, White FM, et al. 14-3-3sigma controls mitotic translation to facilitate cytokinesis. Nature. 2007;446:329–332. This paper shows that the 14-3-3 protein (gamma isoform) is essential for the down-regulation of cap-dependent translation in mammalian cells during mitosis and that this reduction in translation is necessary for proper mitosis. [PubMed]
**39. Tzur A, Kafri R, LeBleu VS, Lahav G, Kirschner MW. Cell growth and size homeostasis in proliferating animal cells. Science. 2009;325:167–171. This manuscript analyzes the growth parameters of synchronous mammalian cells showing that G1 cells increase their growth the fastest and that there is a reduction in growth at the end of the cell cycle. [PMC free article] [PubMed]
40. Hartwell LH, Culotti J, Pringle JR, Reid BJ. Genetic control of the cell division cycle in yeast. Science. 1974;183:46–51. [PubMed]
41. Pardee AB. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA. 1974;71:1286–1290. [PubMed]
42. Gielchinsky Y, Laufer N, Weitman E, Abramovitch R, Granot Z, Bergman Y, Pikarsky E. Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch. Genes Dev. 24:543–548. [PubMed]
43. Bjorklund M, Taipale M, Varjosalo M, Saharinen J, Lahdenpera J, Taipale J. Identification of pathways regulating cell size and cell-cycle progression by RNAi. Nature. 2006;439:1009–1013. [PubMed]
44. Hemerly A, Engler Jde A, Bergounioux C, Van Montagu M, Engler G, Inze D, Ferreira P. Dominant negative mutants of the Cdc2 kinase uncouple cell division from iterative plant development. Embo J. 1995;14:3925–3936. [PubMed]
45. Burg TP, Godin M, Knudsen SM, Shen W, Carlson G, Foster JS, Babcock K, Manalis SR. Weighing of biomolecules, single cells and single nanoparticles in fluid. Nature. 2007;446:1066–1069. [PubMed]
**46. Godin M, Delgado FF, Son S, Grover WH, Bryan AK, Tzur A, Jorgensen P, Payer K, Grossman AD, Kirschner MW, et al. Using buoyant mass to measure the growth of single cells. Nat Methods. 7:387–390. Using the SMR method, the authors measured the growth rates of single cells from several different organisms. They observe that growth is proportional to cell size. [PMC free article] [PubMed]