Summary
Genetic intervention in cell-cycle regulation is a promising strategy to obtain mammalian cell culture proliferation in the absence of exogenous growth factors. In order to gain insights into this approach, known interactions among the four proteins cyclin E, cdk2, the retinoblastoma gene product (RB), and the transcription factor E2F, all centrally involved in control of the G1/S transition of the eucaryotic cell cycle, guided the formulation of kinetics in intracellular mass balances on these components. Stable oscillatory solutions of these equations, which include the diluting effects of cell volume increase and a resulting special boundary condition, correspond to cell proliferation. The model simulates the qualitative consequences on cell cycle regulation of overexpression of cyclin E, E2F, and of RB deregulation in agreement with experiment. Bifurcation analysis of the model suggests strategies for rational manipulation of the cell cycle.
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References
Bailey, J.E. and Ollis, D. (1986). Biochemical Engineering Fundamentals, 2 ed., New York: McGraw-Hill.
Cooper, J. and Whyte, P. (1989). Cell 58, 1009.
Fredrickson, A. (1976). Biotech. Bioeng. 28, 1481.
Goldbeter, A. (1991). Proc. Natl. Acad. Sci. USA 88, 9107.
Hatzimanikatis, V., Lee, K.H., and Bailey, J.E. (1995). Manuscript in preparation.
Knoblich, J.A., Sauer, K., Jones, L., Richardson, Saint, R. and Lehner, C.F. (1994). Cell 77, 107.
Lee, K.H. (1995). Ph.D. thesis, California Institute of Technology.
Lees, E., Faha, B., Dulic, V., Reed, S., and Harlow, E. (1992). Genes Dev. 6, 1874.
Lin, B. and Wang, Y. (1992). In: Regulation of the Eukaryotic Cell Cycle, J. Marsh, ed. vol. 170. pp. 227–243, New York: Wiley.
Matsushime, H., Roussel, M.F., Ashmun, R.A., and Sherr, C. (1991). Cell 65, 701.
Murray, A. and Kirschner, M. (1989). Science 246, 614.
Norel, R. and Agur, Z. (1991). Science 251, 1076.
Novak, B. and Tyson, J. (1993). J. Cell Sci. 106, 1153.
Nurse, P. (1990). Nature 344, 503.
Pagano, M., Draetta, G., Jansen-Dürr, P. (1992). Science 255, 1144.
Peeper, D.S., van der Eb, A.J. and Zantema, A. (1994). Biochim. Biophys. Acta 1198, 215.
Renner, W. A., Lee, K.H., Hatzimanikatis, V., Bailey, J.E., and Eppenberger, H.M. (1995). Biotech. Bioeng., in press.
Tyson, J. (1993). J. Theor. Biol. 165, 101.
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Hatzimanikatis, V., Lee, K.H., Renner, W.A. et al. A mathematical model for the G1/S transition of the mammalian cell cycle. Biotechnol Lett 17, 669–674 (1995). https://doi.org/10.1007/BF00130348
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DOI: https://doi.org/10.1007/BF00130348