Figure 1.

(A) Qualitative network showing mutual antagonism between AKT and p53. An arrow means a pathway that leads to activation or upregulation; a hammerhead represents inhibition or downregulation. AKT is antagonized by p53 via edges 1–3, and p53 is antagonized by AKT via edges 4–5. A p53-MDM2 negative feedback loop is shown by edges 5 and 6. (B) The oscillatory p53-AKT model (the Model). The rate expressions v_i's are given in Table 1. Note: mdm2 and pten denote mRNAs of MDM2 and PTEN gene, respectively. Mechanisms of the p53-AKT mutual antagonism: the network is activated by two cellular events namely growth factor stimulation and cellular stress. The former leads to phosphorylation of PIP2 (phosphatidyl inositol-4,5-bisphosphate) to PIP3 (Phosphatidyl inositol 3,4,5. triphosphate) and thereby PIP3-mediated activation of AKT [43]. Active AKT (AKTa) phosphorylates MDM2 leading to MDM2a translocation to the nucleus [44] where it inhibits p53, and thereby promotes cell survival [45]–[50]. Under cellular stress however, transcriptionally active p53 induces PTEN [51]–[54] among other target genes [55]. PTEN antagonizes AKT-mediated cell survival by deactivating PIP3 through efficient dephosphorylation [56]. p53-dependent transcription of PTEN upon irradiation-induced DNA damage has been reported in MCF-7 (human breast cancer epithelial), A172 (human glioblastoma), MEF (mouse embryonic fibroblasts) and tissues of mouse small intestine, colon, kidney and liver [57]–[59] where p53 oscillations are also observed [1], [3]–[5], [60].