A series of recent studies on large-scale networks of signaling and metabolic systems revealed that a certain network structure often called “bow-tie network” are observed. In signaling systems, bow-tie network takes a form with diverse and redundant inputs and outputs connected via a small numbers of core molecules. While arguments have been made that such network architecture enhances robustness and evolvability of biological systems, its functional role at a cellular level remains obscure. A hypothesis was proposed that such a network function as a stimuli-reaction classifier where dynamics of core molecules dictate downstream transcriptional activities, hence physiological responses against stimuli. In this study, we examined whether such hypothesis can be verified using experimental data from Alliance for Cellular Signaling (AfCS) that comprehensively measured GPCR related ligands response for B-cell and macrophage. In a GPCR signaling system, cAMP and Ca2+ act as core molecules. Stimuli-response for 32 ligands to B-Cells and 23 ligands to macrophages has been measured. We found that ligands with correlated changes of cAMP and Ca2+ tend to cluster closely together within the hyperspaces of both cell types and they induced genes involved in the same cellular processes. It was found that ligands inducing cAMP synthesis activate genes involved in cell growth and proliferation; cAMP and Ca2+ molecules that increased together form a feedback loop and induce immune cells to migrate and adhere together. In contrast, ligands without a core molecules response are scattered throughout the hyperspace and do not share clusters. G-protein coupling receptors together with immune response specific receptors were found in cAMP and Ca2+ activated clusters. Analyses have been done on the original software applicable for discovering ‘bow-tie’ network architectures within the complex network of intracellular signaling where ab initio clustering has been implemented as well. Groups of potential transcription factors for each specific group of genes were found to be partly conserved across B-Cell and macrophage. A series of findings support the hypothesis.

Alpha-arbutin (4-hydroxyphenyl alpha-glucopyranoside) is a known inhibitor of tyrosinase in keratinocytes; however, its effect on other genes and pathways in other skin cells has not been thoroughly investigated. In this study, we investigate the mechanism of alpha-arbutin activity in human dermal fibroblast cultures for 48 h. Results showed that the oxidative stress pathway was activated as alpha-arbutin reduced reactive oxygen species. In addition, we found a high possibility of wound healing and the upregulation of the insulin-like growth factor 1 receptor (IFG1R) pathway. We also investigated the role of the NRF2 gene in mediating the alpha-arbutin response. In silico comparative genomics analysis conducted using our original tool, SHOE, suggested transcription factors with a role in tumor suppression and toxicity response as candidates for regulating the alpha-arbutin–mediated pathway.

The identification of cis-elements (motifs) in the regulatory regions of higher eukaryotes is an important and challenging problem in computational biology. Eukaryotic transcriptional regulatory mechanisms pose several difficulties for promoter analysis: including a high variance in the motif locations, frequently large divergence from motif consensus patterns, and a large amount of repetitive elements (confusing to many motif finding procedures). One promising approach to this difficult problem involves cross-species comparison. In this work we analyzed the full-length regulatory regions of genes involved in the G-protein coupling MAP kinase pathway and compared the results with ribosomal genes using human, mouse and rat genomic data. We found 19 high likely transcription factors (TFs) candidates for MAPK and 12 TFs for the ribosomal dataset. In the case of the MAPK dataset, regulatory regions of genes functionally grouped as receptors and MAP-core genes were found mostly highly conserved across the three species.