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A mathematical model of the effects of hypoxia on the cell-cycle of normal and cancer cells

By T. Alarcon, H. M. Byrne and P. K. Maini

Abstract

The evolution of the cell-cycle is known to be influenced by environmental conditions, including lack of extracellular oxygen (hypoxia). Notably, hypoxia appears to have different effects on normal and cancer cells. Whereas both experience hypoxia-induced arrest of the G1 phase of the cell-cycle (i.e. delay in the transition through the restriction point), experimental evidence suggests that only cancer cells undergo hypoxia-induced quiescence (i.e. the transition of the cell to a latent state in which most of the cell functions, including proliferation, are suspended). Here, we extend a model for the cell-cycle due to Tyson and Novak (J. Theor. Biol. 210 (2001) 249) to account for the action of the protein p27. This protein, whose expression is upregulated under hypoxia, inhibits the activation of the cyclin dependent kinases (CDKs), thus preventing DNA synthesis and delaying the normal progression through the cell-cycle. We use a combination of numerical and analytic techniques to study our model. We show that it reproduces many features of the response to hypoxia of normal and cancer cells, as well as generating experimentally testable predictions. For example our model predicts that cancer cells can undergo quiescence by increasing their levels of p27, whereas for normal cells p27 expression decreases when the cellular growth rate increases

Topics: Biology and other natural sciences
Year: 2004
DOI identifier: 10.1016/j.jtbi.2004.04.016
OAI identifier: oai:generic.eprints.org:363/core69

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Citations

  1. (2000). Bcl-2 in cell-cycle regulation of hematopoietic cells quiescent cells from multicellular spheroids.
  2. (1999). Cancer cell-cycle control.
  3. (1995). Cellular targets for activation by the E2F1 transcription factor include DNA synthesis and G1=S-regulatory genes.
  4. (1999). Cyclin A is a functional target of retinoblastoma tumour suppressor protein-mediated cell-cycle arrest.
  5. (1998). Differentiation and proliferation of primary rat hepatocytes cultured as spheroids.
  6. (1995). Ectopic expression of cyclin E in estrogen responsive cell abrogates antiestrogeb mediated growth arrest.
  7. (2001). Estimating the selective advantage of mutant p53 tumour cells to repeated rounds of hypoxia.
  8. (1995). Evolution of the cell-cycle.
  9. (2000). How to make a biological switch.
  10. (1998). Hypotonic Ca2รพ signaling and volume regulation in proliferating and ARTICLE IN PRESS T. Alarc !on et al.
  11. (1999). Hypoxia and reoxygenation: a pressure for mutant p53 cell selection and tumour progression.
  12. (2001). Hypoxia inhibits G1=S transition through regulation of p27 expression.
  13. (1996). Life (and death) in a malignant tumour.
  14. (2001). Lovastatin-induced E2F-1 modulation and its effect on prostate cancer cell death.
  15. (2003). Low expression of p27 indicates a poor prognosis in patients with high garde astrocytomas.
  16. Low expression of p27 protein combined with altered p53 and Rb/ p16 expression status is associated with increased expression of cyclin A and cyclin B1 in diffuse B-cell lymphoma.
  17. (2002). Modelling avascular tumour growth with a hybrid cellular automaton.
  18. (1992). Numerical Recipes in C.
  19. (2001). p27(Kip1): regulation and function of haploinsufficient tumour supressor and its misregulation in cancer.
  20. (2002). Phosphorylation of pRb is required for HGF-induced muscle cell proliferation and is p27(kip1)-dependent.
  21. (2001). Regulation of FRTL-5 thyroid cell growth by phosphatidylinositol (OH) 3 kinase-dependent Akt-mediated signaling.
  22. (2001). Regulation of the eukariotic cell-cycle: molecular antagonism, hysteresis, and irreversible transitions.
  23. (1998). Response of tumour cells to hypoxia: role of p53 and NFkB.
  24. (1973). Self-regulation of growth in three dimensions.

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