Control of Cell Cycle and Cell Growth by Molecular Chaperones

[Cell Cycle 6:21, 2599-2603, 1 November 2007]; ©2007 Landes Bioscience

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Control of Cell Cycle and Cell Growth by Molecular Chaperones Martí Aldea* Eloi Garí Neus Colomina

Abstract

Original manuscript submitted: 08/05/07 Revised manuscript submitted: 08/17/07 Manuscript accepted: 08/19/07 Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/4920

Introduction

Acknowledgements

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We thank Francisco Ferrezuelo, Jordi Torres, Carme Gallego and Paul Nurse for helpful discussions. This work was funded by the Ministry of Education and Science of Spain, Fundació La Caixa and the European Union (FEDER). N.C. is a researcher of the Ramon y Cajal programme.

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cell cycle, Start, critical cell size, growth rate, chaperones, Cln3, Ydj1

Cell size is generally considered as the outcome of complex parallel processes more or less interconnected and/or interdependent that, in turn, transmit different sorts of intrinsic and extrinsic information. Among these processes, cell growth and cell cycle are particularly relevant as they likely apply to all cellular models, and excellent reviews have been written in the last years that deal with the mechanisms that coordinate growth and division as a fundamental biological problem.1‑9 Here we will focus on the mechanisms that ensure cell size homeostasis during proliferation as a function of intrinsic cues in budding yeast. This unicellular model system displays two of the most universal credentials regarding cell size control: (1) a critical size threshold for cell cycle progression,10,11 and (2) a constant mass/ploidy ratio.12 On the other hand, recent work by our group on the regulation of Cdk/cyclin activity during G113 has interconnected the cell cycle and growth machineries in an unforeseen way that may establish the molecular basis for setting a critical size threshold as a function of the mass/ploidy ratio. In budding yeast, cyclin Cln314‑19 is the most upstream activator of Start,20 where a transcriptional wave driven by two heteromeric transcription factors, SBF (Swi6‑Swi4) and MBF (Mbp1‑Swi6),21 induces the expression of ca. Two hundred genes to trigger cell cycle entry.22 The cyclin Cln3 forms a complex with Cdc28, the cell cycle Cdk in budding yeast, that phosphorylates Whi5 (and presumably Swi6) at multiple residues to activate SBF and MBF‑dependent transcription,23,24 in a squeme homologous to the onset of the mammalian cell cycle, where Cdk4,6‑cyclin D complexes phosphorylate pRB to activate E2F‑DP transcription factors.25 Once discarded the naive possibility of a mechanical sizer, mathematical models of the cell cycle have usually assumed that accumulation of short‑lived molecules should attain a threshold level to trigger a size‑sensitive cell cycle step.26 Since the Cln3 cyclin is extremely unstable17,27 and it is present at rather constant levels throughout G1,17,28 it has been assumed that a progressive and passive accumulation of this G1 cyclin in the nucleus driven by its NLS29,30 would eventually reach a threshold level and trigger Start. However, nuclear and cell volumes increase in parallel during G131 making unlikely such a simple model. Suggesting the existence of far more complex mechanisms linking Cln3 activity to intrinsic size‑information sources during G1, WHI3 was first isolated as a gene involved in cell size regulation that exerted a negative role on Cln3.32 Whi3 contains an RNA‑binding domain that binds the CLN3 mRNA,33 and also recruits Cdc28 to restrain nuclear accumulation of Cln3/Cdc28 complexes in early G1.34 We had hypothesized that Whi3 could restrict CLN3 mRNA translation to a distinct molecular environment that would retain newly‑formed Cdc28‑Cln3 complexes, and hinder their access to the nuclear import

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*Correspondence to: Martí Aldea; Departament de Ciències Mèdiques Bàsiques; IRBLLEIDA, Universitat de Lleida; Lleida, Catalonia, Spain; Email: marti. [email protected]

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Departament de Ciències Mèdiques Bàsiques; IRBLLEIDA, Universitat de Lleida; Lleida, Catalonia, Spain

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Cells adapt their size to both intrinsic and extrinsic demands and, among them, those that stem from growth and proliferation rates are crucial for cell size homeostasis. Here we revisit mechanisms that regulate cell cycle and cell growth in budding yeast. Cyclin Cln3, the most upstream activator of Start, is retained at the endoplasmic reticulum in early G1 and released by specific chaperones in late G1 to initiate the cell cycle. On one hand, these chaperones are rate-limiting for release of Cln3 and cell cycle entry and, on the other hand, they are required for key biosynthetic processes. We propose a model whereby the competition for specialized chaperones between growth and cycle machineries could gauge biosynthetic rates and set a critical size threshold at Start.

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Sizing Cells with Chaperones

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machinery by an unknown mechanism. Recent results from our lab indicate that Cln3 is retained at the cytosolic face of the endoplasmic reticulum (ER) during early G1, thus preventing its unscheduled entry into the nucleus (ref. 13, and see Fig. 1). Efficient binding of Cln3 to the ER requires Whi3 and Cdc28, being a fraction of both also associated to the ER. First, Whi3 would confine translation of the CLN3 mRNA to specific sites of the cytosolic face of the ER, where Cdc28 would be also recruited. Second, as efficient binding of Cln3 to the Cdc28 is an absolute requirement for ER retention, we propose that Cdc28 serves as a bridge between ER‑scaffold structures and the Cln3 cyclin. Cdk‑cyclin complex formation involves the participation of molecular chaperones,35 and we have found that Cln3 interacts with Ssa1,2 (ref. 13, and our unpublished results), two of the most prominent Hsp70 proteins in budding yeast. The ATPase activity of Hsp70 is modulated by Hsp40 chaperones through the so called J domain.36 We have identified in Cln3 an inhibitory version of the J domain (Ji) lacking the HPDK consensus that is essential to activate the ATPase activity of Hsp70.36 The Ji domain of Cln3 is essential for efficient binding to Cdc28 and, hence, for ER retention. Finally, we have found that Ydj1, a J‑protein chaperone previously involved in Cln3 degradation,37 plays a key and limiting role for release of Cln3 from the ER. In our current view at the molecular level, the Ji domain of Cln3 would inhibit the Hsp70 conformational cycle, and lock Ssa1,2 chaperones into a tightly associated ER complex with Cdc28 in early G1, thus preventing unscheduled nuclear import of Cln3. In late G1, once a relative surplus of Ydj1 is achieved, ATPase activation by Ydj1 would unlock the Ssa1,2 complex, and trigger ER release and nuclear accumulation of Cln3 to initiate cell cycle entry (Fig. 1). In summary, and admitting the likely requirement for other limiting factors and folding activities, we propose that budding yeast would trigger Start only after a threshold level of available Ydj1 chaperone is reached. The most significant advances in the last decade regarding cell size control have originated from genome‑wide screens for small

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Figure 1. Cyclin Cln3 is retained at the ER in early G1 and released by the Ydj1 chaperone to trigger cell cycle entry.13 Whi3 contains an RNA‑recognition motif (RRM) that binds the CLN3 mRNA and a Cdc28‑recruitment region (CRR) to locally retain newly formed Cdc28‑Cln3 complexes. By inhibiting their ATPase‑dependent conformational cycle, the Ji domain of Cln3 would lock Ssa1,2 chaperones into a tightly associated ER complex with Cdc28 in early G1, which would prevent uncontrolled nuclear import of Cln3. In late G1, once a relative surplus of Ydj1 (and most likely other folding activities) is achieved, ATPase activation by Ydj1 would unlock the Ssa1,2 complex, thus releasing Cln3 from the ER and allowing its nuclear accumulation to phosphorylate Whi5 and trigger Start.

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single‑gene deletants in budding yeast,38,39 which demonstrated that ribosome biogenesis is per se a negative regulator of Start. Remarkably, alteration of key proteins (Sfp1, Sch9, Ras‑PKA) that activate transcription of ribosomal protein and ribosome biogenesis genes, causes profound changes in the critical cell size.40,41 Their work raised the key question as to how ribosome biogenesis could hinder Start. From what we have learned about the cell cycle machinery, it appears that both ribosome biogenesis and Start might have something in common to compete for, namely specific chaperones. Ydj1 (together with Ssa1,2) has an essential role at the cytosolic face of the translocon to keep polypeptides in a competent state for translocation to the ER lumen,42 a key process for cell wall and membrane growth in budding yeast. On the other hand, as a result of an integrative analysis of high‑throughput data, Kemmeren and colleagues43 have predicted Ydj1 as being functionally involved in translation and ribosome biogenesis. Thus, high ribosome biogenesis rates could compromise, either directly or by increasing translation and ER translocation rates, the availability of Ydj1 to challenge release of Cln3 from the ER and, hence, cell cycle entry. Supporting this idea, we have shown that Ydj1 levels are rate‑limiting for ER release of Cln3 and Start under maximal growth rate conditions.13 Expression levels of Ydj1 and Ssa1,2 chaperones are fairly constant through the cell cycle.44 However, there are some evidences suggesting that chaperone availability may change along the cell cycle. Results obtained from budding and fission yeast support the notion that individual cells grow with linear kinetics, with an abrupt change at a particular moment of the cell cycle.45‑47 This rate change point (RCP) may in part be due to a general gene‑dosage increase caused by DNA replication during S phase.48,49 Since Ydj1‑Ssa1,2 chaperones are a key element of the general ER translocation process, and assuming that cell wall and membranes grow at a constant rate in G1, requirements for ER translocation and dedicated chaperones would be kept constant as well. However, overall chaperone protein levels will increase as the cell grows during G1, eventually leading to a relative excess of folding activity that would in turn facilitate the ER release and nuclear import of the Cln3‑Cdc28 complex. Then, and constituting an additional mechanism to trigger Start in a switch‑like manner, enough Cdc28‑Cln3 should accumulate in the nucleus to phosphorylate Whi5 (and likely Swi6) at multiple residues to elicit the G1/S transcriptional wave.23,24 Later on, when cells execute S phase, a gene‑dosage RCP would suddenly boost protein synthesis and ER translocation rates, thus reducing chaperone availability to leave Cln3 retained at the ER (Fig. 2). As they have already reached enough chaperone levels in the previous cycle, mother cells would immediately enter Start soon after mitotic exit if the growth rate remains the same. Thus, in cooperation with other regulatory mechanisms that have been proposed to inhibit Cln3 expression in daughter cells,50 our model would also comply with one of the key traits of the budding yeast cell cycle, i.e., asymmetrical division.10 Yeast cells respond very rapidly to nutritional changes by different mechanisms that regulate Cln3 levels to coordinate growth and proliferation.51‑55 Thus, lower levels of Cln3 are produced at lower growth rates, and this correlation would explain why slowly‑growing cells stay longer in G1. However, cell size is smaller at lower growth rates, indicating that relatively much lower amounts of Cln3 are required to trigger cell cycle entry when cells grow slower. This paradox was elegantly solved by Tyers and coworkers,38,41 proposing

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Figure 3. Cell volume as a function of growth rate. In a comprehensive study, Tyson and colleagues56 measured generation times, average cell volumes and budding indexes for a large set of growth conditions. Here we have grouped average cell volumes into seven categories as a function of the generation time from 70 to 210 min, and mean values are plotted as empty circles. Vertical and horizontal error bars correspond to the s.d. for average cell volumes and generation times, respectively, in each category. Theoretical average cell volumes for each generation time were calculated assuming that volume at Start is proportional to growth rate (see Appendix), and are plotted as closed circles.

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that the ribosome biogenesis rate determines the critical size threshold. Thus, yeast cells would set their size depending on how fast protein is made, supporting the notion that what is measured is not size but biosynthetic capacity. In other words, yeast cells would use a speedometer, rather than a ruler, to set a critical size threshold and link growth and proliferation. We have proposed that chaperone availability could link ribosome biogenesis (and other key biosynthetic activities as well) to the cell cycle machinery to regulate Start (ref. 13, and see above). Thus, the level of available specific chaperones would gauge whether the cell has grown big enough to enter the cell cycle and, as the postulated speedometer, would receive direct and indirect inputs transmitting growth rate, i.e., ribosome, cell wall and membrane synthesis as heavy consumers of chaperone function. One of the simple corollaries derived from this proposal is that volume at Start would be proportional to growth rate. The faster the cell grows, the larger it must grow to accumulate enough chaperone levels to overcome constant growth demands, and release Cln3 from the ER to trigger cell cycle entry. This idea can be further tested by predicting average cell size in asynchronous populations as a function of growth rate. We have used existing experimental data56 regarding cell size dependence on growth rate in budding yeast, and calculated average cell volumes of asynchronous populations from corresponding budding indexes,56 a minimal birth volume (extrapolated from the same experimental data as well), and a best‑fit slope to complete a linear function between cell volume at Start and growth rate (see Appendix for details). As shown in Figure 3, this simple assumption may explain most of the cell volume variation over a wide range of growth rates in budding yeast. As the derived equations would predict cell volumes smaller than those observed at very low growth rates, additional parameters are likely involved under very poor nutritional conditions. According to this idea, Johnston and

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Figure 2. Start as a result of the competition for specialized chaperones between growth and cycle machineries. (Top) Key growth processes such as synthesis of cell wall and membranes (and likely ribosomes as well) require the participation of Ydj1. Ydj1 expression is rather constant and accumulates continuously in the cell throughout G1. However, a constant growth rate would require a constant amount of Ydj1 as well, eventually leading to a surplus of this specialized chaperone as the cell grows in G1. Thus, as it is limiting for ER release of Cln3, Ydj1 would have a key role in setting a critical cell size at Start. (Bottom) The growth pattern of a newborn cell was determined by time‑lapse microscopy (our unpublished results). In agreement with previously published data,45-47 volume growth followed a linear kinetics throughout G1. In addition, growth rate underwent a sudden increase shortly after budding, suggesting the existence of a gene‑dosage RCP as proposed by Mitchison.2,45


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1. Donachie WD, Blakely GW. Coupling the initiation of chromosome replication to cell size in Escherichia coli. Curr Opin Microbiol 2003; 6:146‑50. 2. Mitchison JM. Growth during the cell cycle. Int Rev Cytol 2003; 226:165‑258. 3. Conlon I, Raff M. Control and maintenance of mammalian cell size: Response. BMC Cell Biol 2004; 5:36. 4. In: Hall MN, Raff M, Thomas G, eds. Cell Growth: Control of Cell Size. Cold Spring Harbor Laboratory Press, 2004. 5. Jorgensen P, Tyers M. How cells coordinate growth and division. Curr Biol 2004; 14: R1014‑27. 6. Cavalier‑Smith T. Economy, speed and size matter: Evolutionary forces driving nuclear genome miniaturization and expansion. Ann Bot 2005; 95:147‑75. 7. Grebien F, Dolznig H, Beug H, Mullner EW. Cell size control: New evidence for a general mechanism. Cell Cycle 2005; 4:418‑21. 8. Baserga R. Is cell size important? Cell Cycle 2007; 6:814‑6. 9. Zaritsky A, Vischer N, Rabinovitch A. Changes of initiation mass and cell dimensions by the ‘eclipse’. Mol Microbiol 2007; 63:15‑21. 10. Hartwell LH, Unger MW. Unequal division in Saccharomyces cerevisiae and its implications for the control of cell division. J Cell Biol 1977; 1:422‑35. 11. Johnston GC, Pringle JR, Hartwell LH. Coordination of growth with cell division in the yeast Saccharomyces cerevisiae. Exp Cell Res 1977; 105:79‑98. 12. Mortimer RK. Radiobiological and genetic studies on a polyploid series haploid to hexaploid of Saccharomyces cerevisiae. Rad Research 1958; 9:312‑26. 13. Vergés E, Colomina N, Garí E, Gallego C, Aldea M. Cyclin Cln3 is retained at the ER and released by the J chaperone Ydj1 in late G1 to trigger cell cycle entry. Mol Cell 2007; 26:649‑62. 14. Sudbery PE, Goodey AR, Carter BL. Genes which control cell proliferation in the yeast Saccharomyces cerevisiae. Nature 1980; 288:401‑4. 15. Cross FR. DAF1, a mutant gene affecting size control, pheromone arrest, and cell cycle kinetics of Saccharomyces cerevisiae. Mol Cell Biol 1988; 8:4675‑84. 16. Nash R, Tokiwa G, Anand S, Erickson K, Futcher AB. The WHI1+ gene of Saccharomyces cerevisiae tethers cell division to cell size and is a cyclin homolog. EMBO J 1988; 7:4335‑46. 17. Tyers M, Tokiwa G, Futcher B. Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. EMBO J 1993; 12:1955‑68. 18. Dirick L, Bohm T, Nasmyth K. Roles and regulation of Cln/Cdc28 kinases at the start of the cell cycle of Saccharomyces cerevisiae. EMBO J 1995; 14:4803‑13. 19. Stuart D, Wittenberg C. CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells. Genes Dev 1995; 9:2780‑94. 20. Hartwell LH, Culotti J, Pringle JR, Reid BJ. Genetic control of the cell division cycle in yeast. Science 1974; 183:46‑51. 21. Nasmyth K. At the heart of the budding yeast cell cycle. Trends Genet 1996; 12:405‑12. 22. Futcher B. Transcriptional regulatory networks and the yeast cell cycle. Curr Opin Cell Biol 2002; 14:676‑83. 23. de Bruin RAM, McDonald WH, Kalashnikova TI, Yates IIIrd J, Wittenberg C. Cln3 activates G1‑specific transcription via phosphorylation of the SBF‑bound repressor Whi5. Cell 2004; 117:887‑98. 24. Costanzo M, Nishikawa JL, Tang X, Millman JS, Shub O, Breitkreuz K, Dewar D, Rupes I, Andrews B, Tyers M. CDK activity antagonizes Whi5, an inhibitor of G1/S transcription in yeast. Cell 2004; 117:899‑913. 25. Kaelin Jr WG. Functions of the retinoblastoma protein. Bioessays 1999; 21:950‑8. 26. Chen KC, Calzone L, Csikasz‑Nagy A, Cross FR, Novak B, Tyson JJ. Integrative analysis of cell cycle control in budding yeast. Mol Biol Cell 2004; 15:3841‑62. 27. Yaglom J, Linskens MHK, Sadis S, Rubin DM, Futcher B, Finley D. p34Cdc28‑mediated control of Cln3 cyclin degradation. Mol Cell Biol 1995; 15:731‑40. 28. McInerny CJ, Partridge JF, Mikesell GE, Creemer DP, Breeden LL. A novel Mcm1‑dependent element in the SWI4, CLN3, CDC6, and CDC47 promoters activates M/G1‑specific transcription. Genes Dev 1997; 11:1277‑88. 29. Edgington NP, Futcher B. Relationship between the function and the location of G1 cyclins in S cerevisiae. J Cell Sci 2001; 114:4599‑611. 30. Miller ME, Cross FR. Mechanisms controlling subcellular localization of the G1 cyclins Cln2p and Cln3p in budding yeast. Mol Cell Biol 2001; 21:6292‑311. 31. Jorgensen P, Edgington NP, Schneider BL, Rupes I, Tyers M, Futcher B. The size of the nucleus increases as yeast cells grow. Mol Biol Cell 2007, [Epub ahead of print]. 32. Nash RS, Volpe T, Futcher B. Isolation and characterization of WHI3, a size‑control gene of Saccharomyces cerevisiae. Genetics 2001; 157:1469‑80. 33. Garí E, Volpe T, Wang H, Gallego C, Futcher B, Aldea M. Whi3 binds the mRNA of the G1 cyclin CLN3 to modulate cell fate in budding yeast. Genes Dev 2001; 15:2803‑8.

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the volume at Start (VP) and growth rate (a), such that VP = k . a + Vmin (4) where k is a constant that was obtained by best‑fit approximation to experimental data,56 and Vmin is the minimal volume for daughter cells, which was ca. 8 fl as deduced from the same data set by extrapolation to a =0.

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colleagues57 had observed that cell size at budding was constant at very low growth rates. In this regard, a minimal translation rate for Start has been postulated.10 In addition, regulation of the expression of other G1 cyclins (Cln1,2) would fine tune cell volume as a result of specific nutritional signals.58,59,55 In summary, here we propose that cell size at Start is set by a speedometer where the availability of specialized chaperones would gauge the growth rate attained by specific nutritional and other external conditions. Due to a likely increasing availability of chaperones during G1, this model may help explain how a continuous process of growth during G1 triggers Start as a discontinuous outbreak. In addition, it also adds some molecular basis to understand cell size adaptation to different growth rates. Thus, yeast cells would not have a cell‑size checkpoint per se. Rather, cell size at Start would be a consequence determined by the competition between cycle and growth devices. This possibility would partly reconcile current yeast and animal models, where the existence of a cell‑size checkpoint has been seriously questioned.3,60 Finally, when all external signals and conditions are kept constant, the balance between chaperone levels, as an indicator of cell mass, and biosynthetic capacity, as an indicator of gene dosage, would be an instrument to keep mass/ploidy ratios constant, one of the most universal attribute of cells.

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We have used the probability density function described by Hartwell and Unger10 that expresses the age distribution of budding yeast cells in asynchronously growing populations, and an expanded set of equations developed by Tyson and colleagues56 that establish parental and daughter cell cycle times as a function of the budding index (FB) and the generation time (t) of the whole population. We have considered that individual cells grow following simple bilinear kinetics, with a 2‑fold rate increase at budding time, and used the following equations: Vt=VP(D+P+B‑t)/(D+B) B < t ≤ D (1) Vt=VP(D+P+2B‑2t)/(D+B) 0 < t ≤ B (2) where Vt is the volume of a cell as a function of its age t, the time period until division. P and D correspond to ages of parental and daughter cells when they initiate their respective cycles, and B corresponds to the budding age. VP is the volume of the parental cell when it initiates its cycle, i.e., the volume at Start.10 The average cell volume can be obtained applying equations 1 and 2 to the density function for the age distribution, and integrating between corresponding limits. Hence,

(3)

where a=ln2/t and corresponds to growth rate in relative units. B, P and D periods can be deduced from budding index and generation time (as described Ref. 56). Thus, equation 3 can be solved by integration by parts to express the average cell volume as a function of the volume at Start (VP), the growth rate (a), and the budding index (FB). Finally, we assumed a simple linear dependence between 2602

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