Duplicability-connectivity correlations.

<p>Correlations between gene duplicability and connectivity in six species: <i>H. sapien</i> (Hsap), <i>M. musculus</i> (Mmus), <i>D. melanogaster</i> (Dmel), <i>C. elegans</i> (Cele), <i>S. cerevisiae</i> (Scer), and <i>E. coli</i> (Ecol). The ‘Number of gene families’ row contains, for each species, the number of gene families that had at least one member for that species. The ‘Number of genes’ row contains, for each species, the number of genes covered by the gene families. The value is Spearman’s rank correlation coefficient between duplicability and connectivity, and the -value is computed for the correlation.</p

Duplicability-complexity correlations.

<p>Correlations between gene duplicability and length and between gene duplicability and number of domains, in six species: <i>H. sapien</i> (Hsap), <i>M. musculus</i> (Mmus), <i>D. melanogaster</i> (Dmel), <i>C. elegans</i> (Cele), <i>S. cerevisiae</i> (Scer), and <i>E. coli</i> (Ecol). The numbers of gene families and genes for each of the six species are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044491#pone-0044491-t001" target="_blank">Table 1</a>. The value is Spearman’s rank correlation coefficient between duplicability and connectivity, and the -value is computed for the correlation.</p

Differential and directional estrogenic signaling pathways induced by enterolignans and their precursors

<div><p>Mammalian lignans or enterolignans are metabolites of plant lignans, an important category of phytochemicals. Although they are known to be associated with estrogenic activity, cell signaling pathways leading to specific cell functions, and especially the differences among lignans, have not been explored. We examined the estrogenic activity of enterolignans and their precursor plant lignans and cell signaling pathways for some cell functions, cell cycle and chemokine secretion. We used DNA microarray-based gene expression profiling in human breast cancer MCF-7 cells to examine the similarities, as well as the differences, among enterolignans, enterolactone and enterodiol, and their precursors, matairesinol, pinoresinol and sesamin. The profiles showed moderate to high levels of correlation (<i>R</i> values: 0.44 to 0.81) with that of estrogen (17β-estradiol or E₂). Significant correlations were observed among lignans (<i>R</i> values: 0.77 to 0.97), and the correlations were higher for cell functions related to enzymes, signaling, proliferation and transport. All the enterolignans/precursors examined showed activation of the Erk1/2 and PI3K/Akt pathways, indicating the involvement of rapid signaling through the non-genomic estrogen signaling pathway. However, when their effects on specific cell functions, cell cycle progression and chemokine (MCP-1) secretion were examined, positive effects were observed only for enterolactone, suggesting that signals are given in certain directions at a position closer to cell functions. We hypothesized that, while estrogen signaling is initiated by the enterolignans/precursors examined, their signals are differentially and directionally modulated later in the pathways, resulting in the differences at the cell function level.</p></div

Differential regulation of cell cycle by lignans.

<p>MCF-7 cells were treated with vehicle (<b>A</b>) or 10 nM E₂ (<b>C</b>), or 10 μM each of lignans (<b>E</b>, <b>G</b>, <b>I</b>, <b>K</b>, and <b>M</b>) for the indicated times. Cell extracts were subjected to Western blot analysis for cyclin D1, CDK4, cyclin E and β-actin (control). The results of three independent experiments are summarized along with the statistical evaluation in panels <b>D</b> (for E₂), and <b>F</b>, <b>H</b>, <b>J</b>, <b>L</b> and <b>N</b> (for lignans). Statistical significance of data compared with the negative control (lane 1) is shown as * (<i>p</i> < 0.05).</p

Duplicability-connectivity correlations in simulations.

<p>Spearman’s rank correlation coefficient () between gene duplicability and gene connectivity for different settings under the subfunctionalization model (model Ib in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044491#pone.0044491-Innan1" target="_blank">[5]</a>) and the neofunctionalization model (model IIc in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044491#pone.0044491-Innan1" target="_blank">[5]</a>). The parameter values in each of the four settings are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044491#pone-0044491-t002" target="_blank">Table 2</a>.</p

Potential signaling pathways induced by lignans.

<p>Potential signaling pathways induced by lignans.</p

Differential and directional estrogenic signaling pathways induced by enterolignans and their precursors - Fig 1

<p><b>Chemical structure (A) and cell-proliferation assay (B) for lignans.</b> (<b>A</b>) The phenylpropane backbone is shadowed. (<b>B</b>) MCF-7 cells were treated with vehicle (dimethylsulfoxide, DMSO), E₂ (10 nM) or different concentrations of chemicals as indicated: 1, 1 nM; 2, 10 nM; 3, 100 nM; 4, 1 μM; 5, 10 μM; and 6, 100 μM (on the left), and 10 μM EL (on the right). After incubation for 72 h, cell proliferation was examined by sulforhodamine B (SRB) assay. The rates of cell proliferation in response to E₂ or lignans to that of a control (DMSO) are shown in the graph. *: <i>p</i> < 0.05; vs. control (C), #: <i>p</i> < 0.05; vs. E₂, or §: <i>p</i> < 0.05; vs. EL. ICI: ICI 182,780, an ER antagonist.</p

Duplicability-connectivity correlations vs. genome sizes and evolutionary relationship.

<p>Spearman’s rank correlation coefficient () between gene duplicability and gene connectivity for six species: <i>H. sapien</i> (Hsap), <i>M. musculus</i> (Mmus), <i>D. melanogaster</i> (Dmel), <i>C. elegans</i> (Cele), <i>S. cerevisiae</i> (Scer), and <i>E. coli</i> (Ecol). The evolutionary relationship of the species is based in part on <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044491#pone.0044491-Paps1" target="_blank">[46]</a>. Genome size (in Mbp) information for all species, except <i>E. coli</i>, were obtained from the Animal Genome Size Database and the Fungal Genome Database.</p

Parameters and results for four simulation settings under the subfunctionalization model (model Ib in [5]) and neofunctionalization model (model IIc in [5]).

<p>Fraction of edge loss indicates the number of edges that a duplicated gene loses, when it undergoes subfunctionalization, as a proportion of the number of that gene’s existing edges. Fraction of edge gain indicates the number of new edges a duplicated gene gains, when it acquires a new function, as a proportion of the number of that gene’s existing edges. The correlations are calculated by applying Spearman’s rank correlation. (p-values are less than .).</p

Parameter settings used in the simulations (units for all rates are “per gene per generation”).

<p>Parameter settings used in the simulations (units for all rates are “per gene per generation”).</p