Myxococcus xanthus is a bacterium that undergoes multicellular development requiring coordinate regulation of multiple signaling pathways. One pathway governs aggregation and sporulation of some cells in a starving population and requires C-signaling, whereas another pathway causes programmed cell death and requires the MazF toxin. In response to starvation, the levels of the bifunctional transcription factor/antitoxin MrpC and its related proteolytic fragment MrpC2 are increased, inhibiting the cell death pathway via direct interaction of MrpC with MazF. Herein, we demonstrate that MrpC2 plays a direct role in the transcriptional response to C-signaling. We show that MrpC2 binds to sequences upstream of the C-signal-dependent fmgA promoter. These sequences are present in other C-signal-dependent promoter regions, indicating a general role for MrpC2 in developmental gene regulation. Association of MrpC and/or MrpC2 with the fmgA promoter region in vivo requires FruA, a protein that is similar to response regulators of 2-component signal transduction systems, but may not be phosphorylated. DNA binding studies showed that this association likely involves an unusual mechanism for a response regulator in which FruA and MrpC2 bind cooperatively to adjacent sites upstream of the fmgA promoter. We propose that this unusual mechanism of combinatorial control allows coordination of morphogenetic C-signaling with starvation signaling and cell death, determining spatiotemporal gene expression and cell fate.bacterial development ͉ C-signaling ͉ cell fate ͉ signal transduction ͉ sporulation

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VP16 is a virion phosphoprotein of herpes simplex virus and a transcriptional activator of the viral immediate-early (IE) genes. We identified four novel VP16 phosphorylation sites (Ser18, Ser353, Ser411, and Ser452) at late times in infection but found no evidence of phosphorylation of Ser375, a residue reportedly phosphorylated when VP16 is expressed from a transfected plasmid. A virus carrying a Ser375Ala mutation of VP16 was viable in cell culture but with a slow growth rate. The association of the mutant VP16 protein with IE gene promoters and subsequent IE gene expression was markedly reduced during infection, consistent with prior transfection and in vitro results. Surprisingly, the association of Oct-1 with IE promoters was also diminished during infection by the mutant strain. We propose that Ser375 is important for the interaction of VP16 with Oct-1, and that the interaction is required to enable both proteins to bind to IE promoters.

Background: Free fatty acids (FFA) and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of many obesity-related metabolic disorders. When human hepatoblastoma cells (HepG2) were exposed to different types of FFA and TNF-α, saturated fatty acid was found to be cytotoxic and its toxicity was exacerbated by TNF-α. In order to identify the processes associated with the toxicity of saturated FFA and TNF-α, the metabolic and gene expression profiles were measured to characterize the cellular states. A computational model was developed to integrate these disparate data to reveal the underlying pathways and mechanisms involved in saturated fatty acid toxicity.

Background: The ability to obtain profiles of gene expressions, proteins and metabolites with the advent of high throughput technologies has advanced the study of pathway and network reconstruction. Genome-wide network reconstruction requires either interaction measurements or large amount of perturbation data, often not available for mammalian cell systems. To overcome these shortcomings, we developed a Three Stage Integrative Pathway Search (TIPS © ) approach to reconstruct context-specific active pathways involved in conferring a specific phenotype, from limited amount of perturbation data. The approach was tested on human liver cells to identify pathways that confer cytotoxicity.