Analysis of Regulatory and Interaction Networks from Clusters of Co-expressed Genes - Clustering Challenges in Biological Network - page 74

speculatively associated with the observed robustness of biological systems, in the
sense that the central hubs provide pathways for connecting various components
of the network with similar effectiveness when nodes in the network have been
randomly eliminated or disabled [77]. However, elimination of the major hubs,
through targeted attacks in the network, has a profound and detrimental effect on
the structure of the network, as can been seen by the rapid increase in network
diameter once key hubs have been removed from our network [43]. Systematic
analyses of combined targeted knock-outs holds significant promise in light of
the realization that controlled disturbances may have significant, albeit non detri-
mental effects on the networks. Thus, the effect of a major hub removal might
be replicated through the compounded effect of multiple node removals, of nodes
of lesser importance, without the complete network melt-down that results from
eliminating a central hub [61]. The latter has not only been explored as means of
analyzing networks but is also currently further analyzed as a potential method for
drug target identification [78].
The analysis identified three major hubs of activity, within our protein inter-
action network, namely interleukin1-beta, prolactin (PRL), and mitogen activated
protein kinase 14 is. Il-1B has been reported to be a dominant cytokine that acts
as a central regulator of the acute inflammatory response, basically through the
production of acute phase proteins [79]. This is evident in the large cascade of
genes influenced through the activities of Il-1B. In addition, one specific cascade
which is initiated through the activity of Il-1B, is that regulated by PRL, another
of the dominant nodes we identified [80]. While Il-1B has the outcome of up-
regulating a variety of genes needed in mediating the acute phase response, PRL
has the inverse effect, in that it aides in the acute phase response by opposing
the immunosuppressive effects of glucocorticoids and other inflammatory medi-
ators to maintain steady-state homeostasis [81, 82]. The third hub we identified,
p38MAPK, has also been established as a prominent gene involved in the acute
phase response [83-86]. The p38 signaling cascade exhibits its effects following
thermal injury, generally through the up-regulation of proinflammatory cytokines,
such as the aforementioned Il-1B [87]. Thus, not only are these hubs capable of
regulating a variety of down-stream genes, they themselves exhibit a high-degree
of cross-talk, and regulate each other within the overall context of the protein in-
teraction network. In addition, identification of these hubs provides potential ther-
apeutic targets, to mitigate the inflammatory response observed following thermal
injury.