Functional capabilities of molecular network components controlling the mammalian G1/S cell cycle phase transition.

The molecular interactions implicated in the mammalian G1/S cell cycle phase transition comprise a highly nonlinear network which can produce seemingly paradoxical results and make intuitive interpretations unreliable. A new approach to this problem is presented, consisting of (1) a convention of unambiguous reaction diagrams, (2) a convenient computer simulation method, and (3) a quasi-evolutionary method of probing the functional capabilities of simplified components of the network. Simulations were carried out for a sequence of hypothetical primordial systems, beginning with the simplest plausibly functional system. The complexity of the system was then increased in small steps, such that functionality was added at each step. The results suggested new functional concepts: (1) Rb-family proteins could store E2F in a manner analogous to the way a condenser stores electric charge, and, upon phosphorylation, release a large wave of active E2F; (2) excessive or premature cyclin-dependent kinase activities could paradoxically impair E2F activity during the G1/S transition period. The results show how network simulations, carried out by means of the methods described, can assist in the design and interpretation of experiments probing the control of the G1/S phase transition.