An expansion to >200 CGG/CCG repeats (hereafter called CGG) in the 5' region of the FMR1 gene causes fragile X syndrome, and this locus becomes a folate-sensitive fragile site. We used Saccharomyces cerevisiae as a model system to study the stability and fragility of CGG repeats. Tracts of (CGG)(81)and (CGG)(160)were integrated onto a yeast chromosome in both orientations relative to the nearest replication origin. Tracts of this length are pre-mutation alleles in humans, with a high probability of expansion in future generations. The CGG tracts in yeast colonies showed a length-dependent instability with longer tracts being more prone to contraction than shorter tracts. In addition, there was an orientation bias for tract stability with tracts having fewer contractions when the CCG strand was the template for lagging strand synthesis. Expansions of the CGG tracts also occurred in an orientation-dependent manner, although at a lower frequency than contractions. To determine whether CGG tracts are fragile sites in yeast, the CGG tracts were flanked by direct repeats, and the rate of recombination between the repeats determined. Strains carrying the (CGG)(160)tract in either orientation had a large increase in their rate of recombination compared with a no-tract control strain. Because this increase was dependent on genes involved in double-strand break repair, recombination was likely to be initiated by CGG tract-induced breakage between the direct repeats. The observation of orientation-dependent instability and orientation-independent fragility suggests that at least some aspects of their underlying mechanisms are different.
The use of genomic predictors of response to cisplatin and pemetrexed can be incorporated into strategies to optimize therapy for advanced solid tumors.
Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycininduced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.
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