A Structural Analysis of the Qualitative Networks Regulating the Cell Cycle and Apoptosis

Abstract

This paper proposes an integration and modular organization of the complex regulatory networks involved in the mammalian cell cycle, apoptosis, and related intracellular signaling cascades. A common node linking the cell cycle and apoptosis permits the possibility of coordinate control between the initiation of these two cellular processes. From this node, pathways emanate that lead to the activation of cyclin-dependent kinases (in the cell cycle) and caspases (in apoptosis). Computer simulations are carried out to demonstrate that the proposed network architecture and certain module-module interactions can account for the experimentally observed sequence of cellular events (quiescence, cell cycle, and apoptosis) as the transcriptional activities of E2F-1 and c-Myc are increased. Despite the lack of quantitative kinetic data on most of the pathways, it is demonstrated that there can be meaningful conclusions regarding system stability that arise from the topology of the network. It is shown that only cycles in the network graph determine stability. Thus, several positive and negative feedback loops are identified from a literature review of the major pathways involved in the initiation of the cell cycle and of apoptosis.

MicroRNA regulation of a cancer network: Consequences of the feedback loops involving miR-17-92, E2F, and Myc

“…Not shown in the figure are pathways downstream of E2F and Myc that lead to caspase-mediated apoptosis (reviewed in ref. 9). Cdk, cyclindependent kinase; pRb, retinoblastoma protein.…”

“…regulatory network coordinating cell cycle entry and apoptosis (9,19). Among the predictions of the model is that increasing levels of E2F or Myc drives the sequence of cellular states, namely, quiescence, cell proliferation, and apoptosis.…”

Mathematical Analysis Of A Modular Network Coordinating The Cell Cycle And Apoptosis

“…Except for the time-scaling factor ε, equations (1)- (5) are identical to those used in [1]. The cyclic reactions shown in Figure 2-namely, those between the pairs of species (S 1 , S 2 ), (C 1 , C 2 ), and (A 1 , A 2 )-imply that the total concentrations of each pair of species is constant.…”

“…Finally, the interaction labeled "c" includes the cell-cycle-enhanced apoptosis via the indirect regulation of caspases by cyclin-dependent kinases (e.g., activation of a caspase by a D-type cyclin, as reported by Mendelsohn et al [7]). More details and justification of these modulemodule interactions are discussed in [1].…”

“…Enhanced cell proliferation can be due to increased cell cycling, inhibited apoptosis, or both. Recently, Aguda and Algar [1] reviewed and analyzed the regulatory molecular pathways linking the initiation of the cell cycle and apoptosis. These authors suggested a modular organization of the complex networks and presented a corresponding kinetic model for the cellular state transitions from quiescence (nondividing) to cell cycling, and eventually to apoptosis as the strength of extracellular signaling increases.…”