Title

Modeling the response of a tumor-suppressive network to mitogenic and oncogenic signals.

Document Type

Article

Publication Date

5-23-2017

JAX Source

Proc Natl Acad Sci U S A 2017 May 23; 114(21):5337-5342

PMID

28484034

DOI

https://doi.org/10.1073/pnas.1702412114

Abstract

Intrinsic tumor-suppressive mechanisms protect normal cells against aberrant proliferation. Although cellular signaling pathways engaged in tumor repression have been largely identified, how they are orchestrated to fulfill their function still remains elusive. Here, we built a tumor-suppressive network model composed of three modules responsible for the regulation of cell proliferation, activation of p53, and induction of apoptosis. Numerical simulations show a rich repertoire of network dynamics when normal cells are subject to serum stimulation and adenovirus E1A overexpression. We showed that oncogenic signaling induces ARF and that ARF further promotes p53 activation to inhibit proliferation. Mitogenic signaling activates E2F activators and promotes Akt activation. p53 and E2F1 cooperate to induce apoptosis, whereas Akt phosphorylates p21 to repress caspase activation. These prosurvival and proapoptotic signals compete to dictate the cell fate of proliferation, cell-cycle arrest, or apoptosis. The cellular outcome is also impacted by the kinetic mode (ultrasensitivity or bistability) of p53. When cells are exposed to serum deprivation and recovery under fixed E1A, the shortest starvation time required for apoptosis induction depends on the terminal serum concentration, which was interpreted in terms of the dynamics of caspase-3 activation and cytochrome c release. We discovered that caspase-3 can be maintained active at high serum concentrations and that E1A overexpression sensitizes serum-starved cells to apoptosis. This work elucidates the roles of tumor repressors and prosurvival factors in tumor repression based on a dynamic network analysis and provides a framework for quantitatively exploring tumor-suppressive mechanisms. Proc Natl Acad Sci U S A 2017 May 23; 114(21):5337-5342.