, 2011) such that Olig2 function (and presumably phosphorylation)

is irrelevant in a p53 null context. Together, these findings indicate that Olig2 phosphorylation at the triple serine motif is present in human glioma and regulates tumor growth in a genetically relevant mouse orthotopic model. What is the molecular mechanism that links Olig2 phosphorylation to neurosphere growth Ion Channel Ligand Library cell line and formation of malignant gliomas? A companion paper by Mehta et al. (2011) describes an intrinsic oppositional relationship between Olig2 and p53. Put briefly, Mehta et al. (2011) show that expression of Olig2 suppresses the posttranslational acetylation of p53, which is known to be required for optimum transcriptional functions (Barlev et al., 2001 and Dornan et al., 2003). Concurrent with hypoacetylation, the interactions of p53 with promoter/enhancer elements of its stereotypical target genes (e.g., p21,·Bax, Mdm2) are much attenuated in wild-type neural progenitors relative to their Olig2-null counterparts. Accordingly, p53-mediated biological responses to genotoxic damage

are suppressed by Olig2. Experiments summarized in Figure 7 show that this oppositional relationship between Olig2 and p53 is regulated by the phosphorylation state of the triple serine motif. Wild-type and also phosphomimetic Olig2 suppress the radiation-induced increase in both total p53 (Figure 7A) and acetylated p53 (Figure 7B). Likewise, wild-type and phosphomimetic Olig2 suppress radiation-induced expression of the canonical p53 target gene p21 (Figure 7C, inset). Concurrent with suppression of p21 expression, wild-type and phosphomimetic Olig2 promote the survival Palbociclib in vitro of irradiated neural progenitors, as noted by Mehta et al. (2011) (Figure 7C).

In marked contrast, phospho null Olig2 is deficient in all of these functions. In previous studies we have shown that basal levels of p21 expression seen in cycling neural progenitor cells are also suppressed by Olig2 (Ligon et al., 2007). As shown in Figure 8A (inset), wild-type and phosphomimetic Olig2 suppress basal levels of p21 protein, whereas phospho null Olig2 shows little or no effect. The phospho Olig2-mediated suppression of p21 protein is exerted largely at transcriptional level, as indicated by diminished expression of p21 mRNA ( Figure 8A). Expression of a p21 luciferase reporter gene is likewise controlled by Olig2 in a phosphorylation ADAMTS5 state-dependent manner ( Figure S8). This suppression of basal state p21 mRNA reflects, at least in part, phospho Olig2-regulated changes in the amount of p53 that is associated with promoter/enhancer elements of the p21 gene ( Figure 8B). The differential loading of p53 onto p21 promoter enhancer element is nuanced but statistically significant and also in good accord with the basal state levels of acetylated p53 seen in Figure 7B. On a final note, the phosphorylation state-dependent effects of Olig2 on neurosphere proliferation noted in Figure 1 are completely dependent on p53 status.