Skip to main content
NCBI home page
Cell Proliferation logoLink to Cell Proliferation
. 2003 Jan 31;32(5):321–335. doi: 10.1046/j.1365-2184.1999.3250321.x

The kinetic origins of the restriction point in the mammalian cell cycle

B D Aguda 1, Y Tang 1
PMCID: PMC6726334  PMID: 10619492

Abstract

Abstract. A detailed model mechanism for the G1/S transition in the mammalian cell cycle is presented and analysed by computer simulation to investigate whether the kinetic origins of the restriction point (R‐point) can be identified. The R‐point occurs in mid‐to‐late G1 phase and marks the transition between mitogendependent to mitogen‐independent progression of the cell cycle. For purposes of computer simulations, the R‐point is defined as the first point in time after mitosis where cutting off mitogen stimulation does not prevent the cell reaching the threshold activity of cyclin‐E/cdk2 required for entry into S phase. The key components of the network that generate a dynamic switching behaviour associated with the R‐point include a positive feedback loop between cyclin‐E/cdk2 and Cdc25A, along with the mutually negative interaction between the cdk inhibitor p27Kip1 and cyclin‐E/cdk2. Simulations of the passage through the R‐point were carried out and the factors affecting the position of the R‐point in G1 are determined. The detailed model also shows various points in the network where the activation of cyclin‐E/cdk2 can be initiated with or without the involvement of the retinoblastoma protein.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

REFERENCES

  1. Aguda BD. (1999) Instabilities in phosphorylation‐dephosphorylation cascades and cell cycle checkpoints. Oncogene 18, 2846. [DOI] [PubMed] [Google Scholar]
  2. Alevizopoulos K, Vlach J, Hennecke S, Amati B. (1997) Cyclin E and c‐Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J. 16, 5322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Almasan A, Yin Y, Kelly RE et al. (1995) Deficiency of pRb leads to inappropriate S‐phase entry, activation of E2F‐responsive genes, and apoptosis. Proc. Natl. Acad. Sci. USA 92, 5436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bartek J, Bartkova J, Lukas J. (1996) The retinoblastoma protein pathway and the restriction point. Curr. Opin. Cell Biol. 8, 805. [DOI] [PubMed] [Google Scholar]
  5. Bartek J, Bartkova J, Lukas J. (1997) The retinoblastoma protein pathway in cell cycle control and cancer. Exptl. Cell Res. 237, 1. [DOI] [PubMed] [Google Scholar]
  6. Bernards R. (1997) E2F: a nodal point in cell cycle regulation. Biochim. Biophys. Acta 1333, M33. [DOI] [PubMed] [Google Scholar]
  7. Campanero MR, Flemington EK. (1997) Regulation of E2F through ubiquitin‐proteosome‐dependent degradation: stabilization by the pRB tumor suppressor protein. Proc. Natl. Acad. Sci. USA 94, 2221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coats S, Flanagan WM, Nourse J, Roberts JM. (1996) Requirement of p27Kip1 for R point control of the fibroblast cell cycle. Science 272, 877. [DOI] [PubMed] [Google Scholar]
  9. Fang X, Jin X, Xu H‐J et al. (1998) Expression of p16 induces transcriptional downregulation of the RB gene. Oncogene 16, 1. [DOI] [PubMed] [Google Scholar]
  10. Feinberg M, Horn FJM. (1974) Dynamics of open chemical systems and the algebraic structure of the underlying reaction network. Chem. Eng. Sci. 29, 775. [Google Scholar]
  11. Galaktionov K, Chen X, Beach D. (1996) Cdc25 cell‐cycle phosphatase as a target of c‐myc. Nature 382, 511. [DOI] [PubMed] [Google Scholar]
  12. Geng Y, Ng Eaton E, Picon M et al. (1996) Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. Oncogene 12, 1173. [PubMed] [Google Scholar]
  13. Hengst L, Reed SI. (1996) Translational control of p27Kip1accumulation during the cell cycle. Science 271, 1861. [DOI] [PubMed] [Google Scholar]
  14. Herrera RE, Sah VP, Williams BO, Makela TP, Weinberg RA, Jacks T. (1996) Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb‐deficient fibroblasts. Mol. Cell. Biol. 16, 2402. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hiebert SW, Lipp M, Nevins JR. (1989) E1A‐dependent transctivation of the human MYC promoter is mediated by the E2F factor. Proc. Natl. Acad. Sci. USA 86, 3594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hoffmann I, Draetta G, Karsenti E. (1994) Activation of the phosphatase activity of human cdc25A by a cdk2‐cyclin E dependent phosphorylation at the G1/S transition. EM BO J. 13, 4302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ikeda M, Jakoi L, Nevins JR. (1996) A unique role for the Rb protein in controlling E2F accumulation during cell growth and differentiation. Proc. Natl. Acad. Sci. USA 93, 3215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Koff A, Giordano A, Desai D et al. (1992) Formation and activation of a cyclin E‐cdk2 complex during the G1 phase of the human cell cycle. Science 257, 1689. [DOI] [PubMed] [Google Scholar]
  19. Kohn KW. (1998) Functional capabilities of molecular network components controlling the mammalian G1/S cell cycle phase transition. Oncogene 16, 1065. [DOI] [PubMed] [Google Scholar]
  20. Krek W, Ewen ME, Shirodkar S, Arany Z, Kaelin WG, Livingston DM. (1994) Negative regulation of the growth‐promoting transcription factor E2F‐1 by a stably bound cyclin A‐dependent protein kinase. Cell 78, 161. [DOI] [PubMed] [Google Scholar]
  21. Leone G, Degregori J, Sears R, Jakoi L, Nevins JR. (1997) Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F. Nature 387, 422. [DOI] [PubMed] [Google Scholar]
  22. Leone G, Degregori J, Jakoi L, Cook JG, Nevins JR. (1999) Collaborative role of E2F transcriptional activity and G1 cyclin‐dependent kinase activity in the induction of S phase. Proc. Natl. Acad. Sci. USA 96, 6626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Li Y, Nichols MA, Shay JW, Xiong Y. (1994) Transcriptional repression of the D‐type cyclin‐dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 54, 6078. [PubMed] [Google Scholar]
  24. Lukas J, Herzinger T, Hansen K et al. (1997) Cyclin E‐induced S phase without activation of the pRb/E2F pathway. Genes Dev. 11, 1479. [DOI] [PubMed] [Google Scholar]
  25. Lundberg AS, Weinberg RA. (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin‐cdk complexes. Molec. Cell. Bio. 18, 753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mittnacht S. (1998) Control of pRB phosphorylation. Curr. Opin. Gen. Dev. 8, 21. [DOI] [PubMed] [Google Scholar]
  27. Moroy T. (1998) Restriction point control in human cancer. Tumordiagn. U. Ther. 19, 93. [Google Scholar]
  28. Neuman E, Flemington EK, Sellers WR, Kaelin WG JR. (1994) Transcription of the E2F1 gene is rendered cell cycle dependent by E2F DNA‐binding sites within its promoter. Mol. Cell. Biol. 14, 6607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Obeyesekere MN, Knudsen ES, Wang JYJ, Zimmerman SO. (1997) A mathematical model of the regulation of the G1 phase of Rb+/+ and Rb−/− mouse embryonic fibroblasts and an osteosarcoma cell line. Cell Prolif. 30, 171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ohtani K, Degregori J, Nevins JR. (1995) Regulation of the cyclin E gene by transcription factor E2F1. Proc. Natl. Acad. Sci. USA 92, 12146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pardee AB. (1974) A restriction point for control of normal animal cell proliferation. Proc. Natl. Acad. Sci. USA 71, 1286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pardee AB (1989) G1 events and regulation of cell proliferation. Science 246, 603. [DOI] [PubMed] [Google Scholar]
  33. Poon RYC, Chau MS, Yamashita K, Hunter T. (1997) The role of Cdc2 feedback loop control in the DNA damage checkpoint in mammalian cells. Cancer Res. 57, 5168. [PubMed] [Google Scholar]
  34. Reed SI. (1996) Cyclin E: in mid‐cycle. Biochim. Biophys. Acta 1287, 151. [DOI] [PubMed] [Google Scholar]
  35. Roussel MF. (1998) Key effectors of signal transduction and G1 progression. Adv. Cancer Res. 74, 1. [DOI] [PubMed] [Google Scholar]
  36. Serrano M. (1997) The tumor suppressor protein p16INK4a . Exptl. Cell Res. 237, 7. [DOI] [PubMed] [Google Scholar]
  37. Sexl V, Diehl JA, Sherr CJ, Ashmun R, Beach D, Roussel MF. (1999) A rate limiting function of Cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2. Oncogene 18, 573. [DOI] [PubMed] [Google Scholar]
  38. Sheaff RJ. (1997. Regulation of mammalian cyclin‐dependent kinase 2 In: Dunphy WG, ed. Cell Cycle Control (Methods in Enzymology, Vol 283). New York : Academic Press, 173. [DOI] [PubMed] [Google Scholar]
  39. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE. (1997) Cyclin E‐CDK2 is a regulator of p27. Genes Dev. 11, 1464. [DOI] [PubMed] [Google Scholar]
  40. Takuwa N, Takuwa Y. (1996) Signal transduction of cell‐cycle regulation: its temporospacial architecture. Jap. J. Physiol. 46, 431. [DOI] [PubMed] [Google Scholar]
  41. Takuwa N, Takuwa Y. (1997) Ras activity late in G1 phase required for p27Kipl downregulation, passage through the Restriction point, and entry into S phase in growth factor‐stimulated NIH 3T3 fibroblasts. Mol. Cell. Biol. 17, 5348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Thalmeier K, Synovzik H, Mertz R, Winnacker EL, Lipp M. (1989) Nuclear factor E2F mediates basic transcription and transactivation by E1A of the human MYC promoter. Genes Dev. 3, 527. [DOI] [PubMed] [Google Scholar]
  43. Tsihlias J, Kapusta L, Slingerland J. (1999) The prognostic significance of altered cyclin‐dependent kinase inhibitors in human cancer. Annu. Rev. Med. 50, 401. [DOI] [PubMed] [Google Scholar]
  44. Vlach J, Hennecke S, Amati B. (1997) Phosphorylation‐dependent degradation of the cyclin‐dependent kinase inhibitor p27Kip1 . EM BO J. 16, 5334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zetterberg A, Larsson O. (1985) Kinetic analysis of regulatory events in G1 leading to proliferation or quiescence of Swiss 3T3 cells. Proc. Natl. Acad. Sci. USA 82, 5365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Zetterberg A, Larsson O, Wiman KG. (1995) What is the restriction point? Curr. Opin. Cell Biol. 7, 835. [DOI] [PubMed] [Google Scholar]

Articles from Cell Proliferation are provided here courtesy of Wiley

RESOURCES