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. 2005 Dec;31(3-4):261–272. doi: 10.1007/s10867-005-6060-x

Determining to Divide: How Do Cells Decide?

Kendall A Smith 1,✉
PMCID: PMC3456348  PMID: 23345898

Abstract

A cell's decision to divide must be regulated with the highest fidelity. Otherwise, abnormalities occurring in the replication of genetic material and cytokinesis would be incompatible with life. It has been known for almost a century that cells comprising a population undergo cellular division at extremely variable rates, even though genetically identical cell clones have been examined. Studies with T lymphocytes at the single cell level have revealed that the rate of cellular division is determined by the accumulation of a critical number of ligand-triggered interleukin-2 (IL2) receptors at the cell surface throughout the G1 phase of the cell cycle. Thus, the cell “counts” the number of triggered IL2 receptors, and only decides to divide when the critical number has been attained. This information is then transferred to the cellular interior via intracellular sensors comprised of D-type cyclins, which ultimately determine when the cell surpasses the “Restriction Point” in late G1, and which commits the cell irrevocably to initiate DNA replication. Beyond the R-point, the cell assembles a definite number of macromolecular pre-replication complexes (Pre-RCs) comprised of at least 6 distinct proteins at sites of the origin of replication on DNA. Complete assembly of the Pre-RCs is a prerequisite for their subsequent disassembly, which must occur before the initiation of DNA strand replication, and which occurs asynchronously throughout the S-phase of the cell cycle and only terminates when the entire DNA has been duplicated. Thus, the fidelity of the decision to divide is exquisitely regulated by macromolecular mechanisms initiated at the cell surface and transferred to the cellular interior so that the cell can make the decision in a quantal (all-or-none) fashion. The question before us is how this quantal decision is made at the molecular level. The available data indicate that the assembly and disassembly of a definite number of large multicomponent macromolecular complexes make the quantal decisions. Here, it is postulated that all fundamental cellular decisions, i.e. survival, death, proliferation and differentiation, are regulated in this fashion. It remains to be determined how the cell counts the signals it receives, and what the molecular forces are that dictate the behavior of macromolecular complexes.

Key words: cell cycle, Restriction point (R-point), interleukin-2 (IL2), Janus kinases (JAK), DNA replication, cyclin, cyclin-dependent kinases (CDK), retinoblastoma (Rb) proteins, quantal

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Footnotes

Alexander Hamilton: “The best security for the fidelity of men, is to make interest coincide with duty.”

References

  1. Rahn O. A Chemical Explanation of the Variability of the Growth Rate. Journal of General Physiology. 1932;15:257–277. doi: 10.1085/jgp.15.3.257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Koch A., Schaecter M. A Model for Statistics of the Cell Division Process. Journal of General Microbiology. 1962;29:435–444. doi: 10.1099/00221287-29-3-435. [DOI] [PubMed] [Google Scholar]
  3. Burns V., Tannock I. On the Existance of a G0 Phase in the Cell Cycle. Cell Tissue Kinetics. 1970;3:321–333. doi: 10.1111/j.1365-2184.1970.tb00340.x. [DOI] [PubMed] [Google Scholar]
  4. Smith, J. and Martin, L.: Do Cells Cycle? Proceedings of National Academic Science United States of America70 (1973), 1263–1269. [DOI] [PMC free article] [PubMed]
  5. Pardee, A., Shilo, B. and Koch, A.: Variability of the cell cycle, in G. Sato and R. Ross (eds.) Hormones and Cell Culture, Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, 1979, pp. 373–392.
  6. Cook J., Cook B. Effect of Nutrients on the Variation of Individual Generation Times. Experiments in Cellular Research. 1962;28:524–534. doi: 10.1016/0014-4827(62)90257-4. [DOI] [PubMed] [Google Scholar]
  7. Pardee A.: A Restriction Point for Control of Normal Animal Cell Proliferation, Proceedings of National Academic Science United States of America71 (1974), 1286–1292. [DOI] [PMC free article] [PubMed]
  8. Cantrell D.A., Smith K.A.The Interleukin-2 T-Cell System: A New Cell Growth Model Science 19842241312–1316.1984Sci...224.1312C [DOI] [PubMed] [Google Scholar]
  9. Baker P.E., Gillis S., Smith K.A. Monoclonal Cytolytic T-Cell Lines. Journal of Experimental Medicine. 1979;149:273–278. doi: 10.1084/jem.149.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Smith K.A., Favata M.F., Oroszlan S. Production and Characterization of Monoclonal Antibodies to Human Interleukin 2: Strategy and Tactics. Journal of Immunology. 1983;131:1808–1815. [PubMed] [Google Scholar]
  11. Leonard W.J., Depper J.M., Uchiyama T., Smith K.A., Waldmann T.A., Greene W.C. A Monoclonal Antibody that Appears to Recognize the Receptor for Human T-Cell Growth Factor; Partial Characterization of the Receptor. Nature. 1982;300:267–269. doi: 10.1038/300267a0. [DOI] [PubMed] [Google Scholar]
  12. Robb R.J., Munck A., Smith K.A. T Cell Growth Factor Receptors. Quantitation, Specificity, and Biological Relevance. Journal of Experimental Medicine. 1981;154:1455–1474. doi: 10.1084/jem.154.5.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Parks, D.R., Bryan, V.M., Oi, V.T. and Herzenberg, L.A.: Antigen-Specific Identification and Cloning of Hybridomas with a Fluorescence-Activated Cell Sorter, Proceedings of National Academic Science United States of America76 (1979), 1962–1966. [DOI] [PMC free article] [PubMed]
  14. Wang H.M., Smith K.A. The Interleukin 2 Receptor. Functional Consequences of its Bimolecular Structure. Journal of Experimental Medicine. 1987;166:1055–1069. doi: 10.1084/jem.166.4.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Rickert M., Boulanger M., Goriatcheva N., Garcia K. Compensatory Energetic Mechanisms Mediating the Assembly of Signaling Complexes Between Interleukin 2 and Its Alpha, Beta and Gamma Receptors. Journal of Molecular Biology. 2004;339:1115–1128. doi: 10.1016/j.jmb.2004.04.038. [DOI] [PubMed] [Google Scholar]
  16. Smith K.A. The Interleukin 2 Receptor. Annual Review of Cellular Biology. 1989;5:397–425. doi: 10.1146/annurev.cb.05.110189.002145. [DOI] [PubMed] [Google Scholar]
  17. Smith K.A. Cell Growth Signal Transduction is Quantal. Annals of the New York Academy of Sciences. 1995;766:263–271. doi: 10.1111/j.1749-6632.1995.tb26674.x. [DOI] [PubMed] [Google Scholar]
  18. Ihle J.N.Cytokine Receptor Signalling Nature 1995377591–594. 10.1038/377591a01995Natur.377..591I [DOI] [PubMed] [Google Scholar]
  19. Moriggl R., Topham D.J., Teglund S., Sexl V., McKay C., Wang D., Hoffmeyer A., Deursen J. van, Sangster M.Y., Bunting K.D., et al. Stat5 is Required for IL-2-Induced Cell Cycle Progression of Peripheral T Cells. Immunity. 1999;10:249–259. doi: 10.1016/S1074-7613(00)80025-4. [DOI] [PubMed] [Google Scholar]
  20. Nakajima H., Liu X-W., Wynshaw-Boris A., Rosenthal L.A., Imada K., Finbloom L.H., Henninghausen L., Leonard W.J. An Indirect Effect of Stat5a in IL2-Induced Proliferation: A Critical Role for Stat5a in IL2-Mediated IL2 Receptor Alpha Chain Induction. Immunity. 1997;7:691–701. doi: 10.1016/S1074-7613(00)80389-1. [DOI] [PubMed] [Google Scholar]
  21. Beadling C., Smith K. DNA Array Analysis of Interleukin-2-Regulated Immediate/Early Genes [epub ahead of print] [Record Supplied By Publisher] Medicine of Immunology. 2002;1:2. doi: 10.1186/1476-9433-1-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Smith, K.: Why do cells count? in L. Matsson (ed.) Nonlinear cooperative phenomena in biological systems Singapore, World Scientific Publishing, 1997, 13–19.
  23. Dutta A., Bell S. Initiation of DNA Replication in Eukaryotic Cells. Annual Review of Cellular and Developmental Biology. 1997;13:293–332. doi: 10.1146/annurev.cellbio.13.1.293. [DOI] [PubMed] [Google Scholar]
  24. Kelly T., Brown G. Regulation of Chromosome Replication. Annual Review of Biochemistry. 2000;69:829–880. doi: 10.1146/annurev.biochem.69.1.829. [DOI] [PubMed] [Google Scholar]
  25. Bell S., Dutta A. DNA Replication in Eukaryotic Cells. Annual Review of Biochemistry. 2002;71:333–374. doi: 10.1146/annurev.biochem.71.110601.135425. [DOI] [PubMed] [Google Scholar]
  26. Turner J. IL2-Dependent Induction of G1 Cyclins in Primary T Cells is not Blocked by Rapamycin or Cyclosporin A. International Immunology. 1993;10:1199–1209. doi: 10.1093/intimm/5.10.1199. [DOI] [PubMed] [Google Scholar]
  27. Martino A., Holmes IV J.H., Lord J.D., Moon J.J., Nelson B.H. Stat5 and Sp1 Regulate Transcription of the Cyclin D2 Gene in Response to IL-2. Journal of Immunology. 2001;166:1723–1729. doi: 10.4049/jimmunol.166.3.1723. [DOI] [PubMed] [Google Scholar]
  28. Sherr C. D-Type Cyclins. Trends in Biochemical Science. 1995;20:187–190. doi: 10.1016/S0968-0004(00)89005-2. [DOI] [PubMed] [Google Scholar]
  29. Sherr C., Roberts J. CDK Inhibitors: Positive and Negative Regulators of G1 Progression. Genes & Development. 1999;13:1501–1512. doi: 10.1101/gad.13.12.1501. [DOI] [PubMed] [Google Scholar]
  30. Harbour J., Dean D. The Rb/E2F Pathway: Expanding Roles and Emerging Paradigms. Genes & Development. 2000;14:2393–2409. doi: 10.1101/gad.813200. [DOI] [PubMed] [Google Scholar]
  31. Kozar K., Ciemerych M., Rebel V., Shigematsu H., Zagozdon A., Sicinska E., Qunyan Y., Yu Q., Bhattacharya S., Bronson R., et al. Mouse Development and Cell Proliferation in the Absence of D Cyclinsm. Cell. 2004;118:477–491. doi: 10.1016/j.cell.2004.07.025. [DOI] [PubMed] [Google Scholar]
  32. Malumbres M., Sotillo R., Santamaria D., Galan J., Cerezo A., Ortega S., Dubus P., Barbacid M. Mammalian Cells Cycle Without the D-type Cyclin-Dependent Kinases cdk4 and cdk6. Cell. 2004;118:493–504. doi: 10.1016/j.cell.2004.08.002. [DOI] [PubMed] [Google Scholar]
  33. Roberts J., Sherr C. Bared Essentials of cdk2 and Cyclin E. Nature Genetics. 2003;35:9–10. doi: 10.1038/ng1234. [DOI] [PubMed] [Google Scholar]
  34. Biggar S., Crabtree G. Cell Signaling Can Direct Either Binary or Graded Transcriptional Responses. EMBO Journal. 2001;20:3167–3176. doi: 10.1093/emboj/20.12.3167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Freeman M., Gurdon J. Regulatory Principles of Developmental Signaling. Annual Review of Cellular and Developmental Biology. 2002;18:515–539. doi: 10.1146/annurev.cellbio.18.012502.083458. [DOI] [PubMed] [Google Scholar]

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