In trying to determine a possible molecular cause for the enhanced REST function, we first examined the likelihood that it http://www.selleckchem.com/products/BIBF1120.html was due to altered Inhibitors,Modulators,Libraries levels of REST expression. The gene encoding REST is located in chromosome 4q12, a re gion of frequent focal amplification in aggressive glioblast omas. Analysis of publicly available Inhibitors,Modulators,Libraries copy number data for 141 glioma tumors, however, found that the amplification of 4q12 was centered around PDGFRA, a known glioma oncogene and not around REST. In these Inhibitors,Modulators,Libraries samples, PDGFRA was the target of frequent focal amplifi cation, often without the coincident amplification of REST, which is located 2,500kb downstream. We next asked if the enhanced REST function was due to increased REST mRNA.

Although Inhibitors,Modulators,Libraries Conti et al found a two to five fold increase in REST mRNA between normal and malig nant tissue, we found no increase in REST mRNA levels in glioma tumors, or correlation between REST mRNA levels and REST target gene expression in the datasets we exa mined. The basis for this discrepancy is not Inhibitors,Modulators,Libraries clear. However given the poor correlation between REST transcript levels and protein levels in gliomas, it is possible that our meta analysis picks up a different, though perhaps overlapping group of tumors than those described in Conti et al. Thus the signature approach would identify glioblatomas that had increased REST function or protein levels in the absence of changes in mRNA levels. Given that heightened REST function is not due to enhanced REST copy number or gene expression, we inves tigated possible post transcriptional mechanisms of regula ting REST function.

In development, REST function is modulated in multiple ways. In neuronal stem cells, loss of REST function is necessary for differentiation into neurons. But before REST is lost at the mRNA level in differen tiating neural stem cells, its function is ablated through the expression of the the F box protein B TrCP, an E3 ubiquitin ligase. B TrCP ubiquitinates REST, selleck chemical Tubacin resulting in its degradation and the de repression of REST target genes. We posited that B TrCP levels maybe similarly regulating REST function in these gliomas. Analysis of gene expres sion levels in normal and neoplastic brain tissues revealed a striking correlation between the expression of REST target genes and B TrCP. This correlation is consistent with the hypothesis that loss of B TrCP expression at the mRNA level plays a role in enhancing REST function by reducing the levels of REST ubiquitination and degradation. Despite their universally poor prognosis, glioblastoma multiformae tumors are quite heterogeneous at the mo lecular level. Recently, the array of recognized molecular subtypes of GBM has expanded to include neural, pro neural, mesenchymal, and classical subtypes.