Within the whole network that is most evident since the Peng Gluta mine Dn record substantially overlaps with almost all MYC related gene sets. The community of this gene set is in the molecular signature map in Extra File 1. Figure S2. Yuneva et al. showed that glutamine but not glucose starvation induces MYC dependent apopto sis in human cancer cells, however the mechanism is unknown. On the other hand, Sensible et al. found that overexpression of MYC promotes glutaminolysis and prospects to cellular addiction to glutamine in cancer cells, These research effects may well result in the growth of targeted killing of cancer cells that depend on high levels of glutamine uptake. We located no report on whether glutamine starvation inhibits the MYC pathway.
If this really is indeed correct, as recommended through the overlapping of these gene sets, then the closely linked nature of glutamine selleck chemical metabolic process along with the MYC pathway will should be eval uated more closely. To more verify the hyperlink involving glutamine depri vation and also the MYC pathway, we downloaded and re analyzed the raw DNA microarray data on glutamine starvation, Working with the GSEA system, we analyzed the whole dataset for enriched gene sets. The enriched gene sets are proven as Supplemental File 1. Table S1. One particular pathway that showed up may be the proteosome degradation pathway, during which nutrient deficient cells suppress professional tein degradation like a suggests for survival. The most noticeable pathways are several MYC target gene sets downregulated at really substantial levels, confirming our observation primarily based on gene set overlaps.
Figure six can be a heatmap of relative expression ranges of the checklist of 42 selleck chemicals MYC target genes compiled from multiple stu dies of MYC transcriptional targets, Glutamine and leucine deficiencies, but not glucose deficiency, strongly downregulate quite a few MYC target genes. The anticancer drug rapamycin features a equivalent result on these genes, sug gesting that rapamycin mimics amino acid starvation. Downregulation is strongest right after 24 hrs of nutrient deficiency, or twelve hrs right after rapamycin remedy. Inter estingly, glutamine and leucine starvation only lead to a modest decrease in MYC gene expression. rapamycin remedy even would seem to upregulate its expression. This raises questions with regards to the mechanism by which these target genes are downregulated. Some hints come from the properly studied effect of rapamycin.
Rapamycin inhibits the TOR pathway, which regulates cell growth and cell cycle progression in lots of species. Rapamycin continues to be proven to downregulate MYC publish transcrip tionally, by inhibiting mRNA translation, Hence, it truly is probable that glutamine starvation would possess a very similar program of action. Glutamine starvation triggers a complicated network of transcription factors which includes ATFs and C EBP components, and this kind of response is likely to be cell line or species depen dent, Indeed, our more evaluation of another set of DNA microarray data suggests that glutamine starvation isn’t going to bring about downregulation of Myc target genes in mouse hepatoma cells, Nevertheless, for this certain B lymphoma cell line studied by Peng et al.