MicroRNAs and Robustness in Biological Regulatory Networks. A Generic Approach with Applications at Different Levels: Physiologic, Metabolic, and Genetic - Systems Biology of Metabolic and Signaling Networks - page 88

Fig. 4.15 Regulation of protein p53 showing relationships with numerous microRNAs with
inhibiting ( green ) or activating ( red ) interactions
cytoskeleton network connected to the Myosin network (in green in Fig. 4.16 )
responsible of the control of morphogenetic processes like the gastrulation
(Almeida and Demongeot 2012 ), the apoptosis and proliferation networks
controlled by the ubiquitous protein p53, inhibited by miRNA302; p53 is a tran-
scription factor of miRNA 34 (Raver-Shapira et al. 2007 ), which is a translation
inhibitor of E2F in the mammal proliferation box (Kohn et al. 2006 ) and of ATPase
and Translocase: p53 is indeed the center of a complex regulatory subnetwork, in
activatory or inhibitory relationship with numerous other microRNAs (Fig. 4.15 ).
The E2F box, the core of the proliferation box (Kohn et al. 2006 ), presents
several attractors both in sequential and parallel updating modes (cf. Fig. 4.14
bottom), especially the periodic behavior (000000001000, 000000010111), when
its nodes are ordered as follows: p27, Cdk2, pCyCE_Cdk2, CyCE_Cdk2, miRNA
159, pCycA_Cdk2, CycA_Cdk2, Rbp-E2F, Rb-E2F, E2F, Rbp, and Rb. The triple
action (accelerate, stop, and slow down the cell cycle) on the proliferation process is
exerted negatively by the gene GATA-6, which is inhibited 1 time out of 2 by
MAPK, and successively positively and negatively (through p53) by the gene
c-MyC which is activated 1 time out of 2 by Erk. Then, the limit cycle of order
4 brought by the negative circuit of size 2 (MKP/Erk) leads the genes MKP, Erk,