HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues during embryonic development. They are also known to behave as oncogenes in some haematological malignancies. In this study, we show that the expression of many of the HOX genes is highly elevated in primary non-small-cell lung cancers (NSCLCs) and in the derived cell lines A549 and H23. Furthermore, blocking the activity of HOX proteins by interfering with their binding to the PBX co-factor causes these cells to undergo apoptosis in vitro and reduces the growth of A549 tumours in vivo. These findings suggest that the interaction between HOX and PBX proteins is a potential therapeutic target in NSCLC

Global Control of Motor Neuron Topography Mediated by the Repressive Actions of a Single Hox Gene

In the developing spinal cord, regional and combinatorial activities of Hox transcription factors are critical in controlling motor neuron fates along the rostrocaudal axis, exemplified by the precise pattern of limb innervation by more than fifty Hox-dependent motor pools. The mechanisms by which motor neuron diversity is constrained to limb levels are, however, not well understood. We show that a single Hox gene, Hoxc9, has an essential role in organizing the motor system through global repressive activities. Hoxc9 is required for the generation of thoracic motor columns, and in its absence, neurons acquire the fates of limb-innervating populations. Unexpectedly, multiple Hox genes are derepressed in Hoxc9 mutants, leading to motor pool disorganization and alterations in the connections by thoracic and forelimb-level subtypes. Genome-wide analysis of Hoxc9 binding suggests that this mode of repression is mediated by direct interactions with Hox regulatory elements, independent of chromatin marks typically associated with repressed Hox genes.National Institutes of Health (U.S.) (P01NS055923

A Boolean network of the crosstalk between IGF and Wnt signaling in aging satellite cells

<div><p>Aging is a complex biological process, which determines the life span of an organism. Insulin-like growth factor (IGF) and Wnt signaling pathways govern the process of aging. Both pathways share common downstream targets that allow competitive crosstalk between these branches. Of note, a shift from IGF to Wnt signaling has been observed during aging of satellite cells. Biological regulatory networks necessary to recreate aging have not yet been discovered. Here, we established a mathematical <i>in silico</i> model that robustly recapitulates the crosstalk between IGF and Wnt signaling. Strikingly, it predicts critical nodes following a shift from IGF to Wnt signaling. These findings indicate that this shift might cause age-related diseases.</p></div

Effects of input factors in signaling cascade.

<p>(A) Based on an initial state where all nodes are inactive, a simulation of a signaling cascade was performed. The model results in an attractor representing an un-stimulated cell. (B) Simulation from an initial state with IGF as single active node results in an attractor representing the young phenotype. (C) In contrast, a simulation of signaling cascade with IGF and Wnt as single active nodes results in an attractor representing a mid-aged phenotype. (D) Simulation of the signaling cascade with Wnt as single active node results in an attractor representing an aged phenotype. Nodes are listed on the y-axis. Time is plotted on the x-axis. Every rectangle represents the state of a node at a specific time: red stands for inactive, green for active.</p

Table of the Boolean functions of the IGF/Wnt crosstalk model.

<p>Table of the Boolean functions of the IGF/Wnt crosstalk model.</p

Crosstalk of IGF and Wnt signaling.

<p>IGF and Wnt signaling are simplified and reduced to their most important nodes. Signaling pathways are highlighted in different colors and the IGF and Wnt sub-networks are depicted by the dashed boxes. Interactions between two molecules are symbolized as black lines. Activation is represented by arrowheads, inhibition by bar-headed arrows. Cellular compartments are separated by grey bars.</p

Attractors of the IGF/Wnt crosstalk model.

<p>Exhaustive attractor search of the IGF/Wnt crosstalk model yielded four single state attractors and one three-states attractor. The frequency of occurrence of each attractor is given as percentage below each column. Each block represents an attractor. The nodes are listed on the y-axis. Each rectangle symbolizes the state of a node: red stands for inactive, green for active.</p