Differential disruption of EWS-FLI1 binding by DNA-binding agents.

Fusion of the EWS gene to FLI1 produces a fusion oncoprotein that drives an aberrant gene expression program responsible for the development of Ewing sarcoma. We used a homogenous proximity assay to screen for compounds that disrupt the binding of EWS-FLI1 to its cognate DNA targets. A number of DNA-binding chemotherapeutic agents were found to non-specifically disrupt protein binding to DNA.

Anti-inflammatory properties of histone deacetylase inhibitors: a mechanistic study.

Background: We have demonstrated that postshock administration of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, can significantly improve early survival in a highly lethal model of hemorrhagic shock. As the primary insult in hemorrhagic shock is cellular hypoxia, and transcription factor hypoxia-inducible factor-1α (HIF-1α) controls proinflammatory gene expression in macrophages, we hypothesized that SAHA would attenuate the HIF-1α associated proinflammatory pathway in a hypoxic macrophage model.

Methods: Mouse macrophages were exposed to hypoxic conditions (0.

Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis.

Although several genes involved in mitochondrial function are direct Myc targets, the role of Myc in mitochondrial biogenesis has not been directly established. We determined the effects of ectopic Myc expression or the loss of Myc on mitochondrial biogenesis. Induction of Myc in P493-6 cells resulted in increased oxygen consumption and mitochondrial mass and function.

Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe.

Expression of the forkhead transcription factor FoxM1 correlates with proliferative status in a variety of normal and transformed cell types. Elevated expression of FoxM1 has been noted in both hepatocellular carcinoma and basal cell carcinoma. However, whether FoxM1 expression is essential for the viability of transformed cells is unknown.

A strategy for identifying transcription factor binding sites reveals two classes of genomic c-Myc target sites.

Defining the hardwiring of transcription factors to their cognate genomic binding sites is essential for our understanding of biological processes. We used scanning chromatin immunoprecipitation to identify in vivo binding regions (E boxes) for c-Myc in three target genes as a model system. Along with other c-Myc target genes that have been validated by chromatin immunoprecipitation, we used the publicly available genomic sequences to determine whether experimentally derived in vivo binding sites might be predictable from nonexonic sequence conservation across species.

The c-Myc target gene PRDX3 is required for mitochondrial homeostasis and neoplastic transformation.

Deregulated expression of the c-Myc transcription factor is found in a wide variety of human tumors. Because of this significant role in oncogenesis, considerable effort has been devoted to elucidating the molecular program initiated by deregulated c-myc expression. The primary transforming activity of Myc is thought to arise through transcriptional regulation of numerous target genes.