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Archive - Oct 21, 2011

Small Molecule Work Advances Progress Toward More Tailored Drugs

Research led by St. Jude Children's Research Hospital scientists advances a strategy for reducing the side effects and enhancing the therapeutic benefits of steroids and other medications that work by disrupting the activity of certain hormones. The approach relies on a small molecule developed at St. Jude. In this study, scientists showed that a compound known as SJ-AK selectively blocked the activity of genes in a cell signaling pathway regulated by thyroid hormone. Investigators showed that SJ-AK also affected cells growing in the laboratory, reducing cell proliferation as well as the production and secretion of a growth hormone regulated by thyroid hormone. The research appears in the October 21, 2011 issue of the scientific journal ACS Chemical Biology. The findings raise hope that compounds like SJ-AK will lead to drugs with more tailored effects by selectively controlling signaling pathways that switch genes on and off. This research focused on a pathway controlled by a thyroid hormone. Investigators said, however, the approach also could potentially be used to target pathways regulated by glucocorticoid, estrogen, androgen, and other hormones that are widely used to treat cancer and other conditions, but that also have serious side effects. "This study offers the first evidence it is possible to shut down a portion of the signaling network activated by a particular hormone," said Dr. R. Kiplin Guy, chair of the St. Jude Chemical Biology and Therapeutics Department. Dr. Guy is the senior author of the paper. The first author is Dr. Prabodh Sadana, a former St. Jude postdoctoral fellow who now works in the Department of Pharmaceutical Sciences at Northeastern Ohio Universities College of Medicine and Pharmacy.

First Complete 3-D Structure of a Bacterial Chromosome

A team of researchers at the University of Massachusetts Medical School, Harvard Medical School, Stanford University, and the Prince Felipe Research Centre in Spain have deciphered the complete three-dimensional (3-D) structure of the bacterium Caulobacter crescentus's chromosome. Analysis of the resulting structure —published this week in the October 21, 2011 issue of Molecular Cell — has revealed new insights into the function of genetic sequences responsible for the shape and structure of this genome. Scientists know that the 3-D shape of a cell's chromosome plays a role in how genetic sequences and genes are regulated. However, technical challenges have limited genome-wide analysis of a chromosome's architecture that would allow for simultaneous identification of the elements involved in shaping it and analysis of specific features of the structure. In this study, researchers used high-throughput chromatin interaction detection; next-generation DNA sequencing; computational modeling; and fluorescent microscopy to build the first 3-D model of the architecture of the bacterium's chromosome and analyze the resulting structures. This new experimental approach revealed novel characteristics of a specific genetic sequence called the parS site, which helps to define the chromosome's shape. "What we've shown is that it's possible to combine molecular biology with 3-D modeling technology to perform studies that tell us novel things about how genomes fold and identify the genetic sequences that are responsible," said Dr. Job Dekker, a pioneer in chromosome interaction detection technologies, professor of biochemistry & molecular pharmacology at the University of Massachusetts Medical School, and one of the authors of the study. Dr.