Transition and identification of pathological states in p53 dynamics for therapeutic intervention.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Cell Biology*; Computational Biology/*methods ; Systems Biology/*methods ; Tumor Suppressor Protein p53/*metabolism; Animals ; Humans ; Tumor Suppressor Protein p53/genetics

We study a minimal model of the stress-driven p53 regulatory network that includes competition between active and mutant forms of the tumor-suppressor gene p53. Depending on the nature and level of the external stress signal, four distinct dynamical states of p53 are observed. These states can be distinguished by different dynamical properties which associate to active, apoptotic, pre-malignant and cancer states. Transitions between any two states, active, apoptotic, and cancer, are found to be unidirectional and irreversible if the stress signal is either oscillatory or constant. When the signal decays exponentially, the apoptotic state vanishes, and for low stress the pre-malignant state is bounded by two critical points, allowing the system to transition reversibly from the active to the pre-malignant state. For significantly large stress, the range of the pre-malignant state expands, and the system moves to irreversible cancerous state, which is a stable attractor. This suggests that identification of the pre-malignant state may be important both for therapeutic intervention as well as for drug delivery.

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File No.R.12014/01/2018-HR Department of Health Research, India

0 (Tumor Suppressor Protein p53)

Date Created: 20210128 Date Completed: 20211012 Latest Revision: 20231104

20231104

PMC7840995

10.1038/s41598-021-82054-1

33504910