Fig 1. Regulation network of the mitotic cell cycle in human cells.

The mitotic biopathway for the reaction network of key mitotic proteins is converted into a mathematical structure based on ODEs involving the law of mass conservations and a hybrid framework combining mass action and Michaelis-Menten kinetics. (A) We have divided the biopathway into three stages (see inset) defined by arrow styles. Each factor, as defined in the text and Supplemental Information, is identified by a unique color conserved throughout the article. Major stages include: (1) Mitotic entry (solid arrows) involving CCNB1, CDK1, preMPF (CCNB1:CDK1P), MPF (CCNB1:CDK1), PLK1, WEE1, CDC25C, PPase (phosphatase), and LMNA, which is a substrate of MPF kinase (P, phosphorylated; NEBD, nuclear envelop breakdown); (2) Metaphase to anaphase transition (double arrows) involving APC/C:CDC20, PPase, and PTTG1 (Securin) in complex with ESPL1 (Separase); and (3) Mitotic exit (dashed arrows) involving APC/CT:CDH1 (T, total). Here, S1 denotes active MPF kinase (CCNB1:CDK1) and S2 denotes active PLK1 kinase (phosphorylated), which are major signals for many mitotic cell cycle reactions, as indicated. Reactions involving Cyclin-dependent kinase inhibitor CDKN1A (p21^CIP1) have been included, and locations for G2 signals and exit into G1 are noted. The model consists of 26 ODEs governing 15 interaction reactions (k_fn forward rate constant and k_rn reverse rate constant for reaction n) of 12 key mitotic proteins and associated protein complexes and includes synthesis (k_s: synthesis rate constant) and multiple degradations (k_dn.1: self-degradation rate constant, k_dn.2: degradation rate constant by APCP/CDC20, and k_dn.3: degradation rate constant by APC/CT:CDH1). (B, C) Simplified wiring diagrams based on (A), which identify both positive (blue, plus symbol) and negative (red, minus symbol) signals regulating the MPF kinase (CCNB1:CDK1) (B), and APC/CP:CDC20 and APC/CT:CDH1 ubiquitin ligase complexes with several signal strengths (C).