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C. elegans
D. melanogaster
mir - 35- 41
LIN 35
RBF2
RBF1
EFL2- DPL1
EFL1- DPL1
dE2F2-dDP
dE2F1-dDP
bantam miRNA
CyE1
Cell prolif eration
G1/S transition
Cell prolif eration
G1/S transition
p53
Mammals
miRNA 34 , miRNA 159
PcG
p130
p107
Rb
E2F6-DP1
E2F5-DP1
E2F4-DP1
E2F3-DP2
E2F2-DP2
E2F1-DP2
Cell prolif eration
G1/S transition
Fig. 4.18 Different control mechanisms of the G1/S transition in different species,
Caenorhabditis elegans , Drosophila melanogaster, and mammals (after Caraguel et al. 2010 )
more difficult to obtain, in particular when two subnetworks create a new strong
connected component, like in the case of the MPK and Cytoskeleton subnetworks
in Fig. 4.16 , which creates a new level of complexity that needs further theoreti-
cal research.
In Fig. 4.18 , a last example shows that the same function (cell proliferation) is
regulated with progressively more frontier nodes of the regulatory networks, when
passing from C. elegans and D. melanogaster to mammals (Caraguel et al. 2010 ;
Kohn et al. 2006 ; Massirer et al. 2012 ; Herranz et al. 2010 ). The progressive
appearance during the evolution of many upstream controllers until the mammals
microRNAs and p53 provides to the cell cycle network a robust Rb-E2F control at
the G1/S transition.
4.7 Conclusion
The sensitivity of real biological networks to endogenous or exogenous
perturbations appears dominant in the case of the inhibitory actions exerted by
the microRNAs and we have noticed this influence for many cases. More
systematic studies have to be performed in order to confirm the dominant
influence of boundary negative interactions, thanks to which the Hopfield-like
regulatory interaction networks seem to become more robust, and also to make
more precise their influence on the number of attractors, which is conjectured to
diminish, when microRNAs are multiple on the boundary of the interaction
graph of the network.
For example, MAPK in Fig. 4.14 is inhibited not only by miR-191 but also by
miR-350 ( http://mirdborg/miRDB/ ; http://mirnamapmbcnctuedutw/ ), which is
also involved in the memory storage and evocation (Smalheiser et al. 2011 ;
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