The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant Glioma

Abstract

SUMMARY High-grade gliomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority of these tumors. Resistance to genotoxic modalities in p53-positive gliomas is generally attributed to attenuation of p53 functions by mutations of other components within the p53 signaling axis, such as p14Arf, MDM2 and ATM, but this explanation is not entirely satisfactory. We show here that the central nervous system (CNS) restricted transcription factor Olig2 affects a key post-translational modification of p53 in both normal and malignant neural progenitors and thereby antagonizes the interaction of p53 with promoter elements of multiple target genes. In the absence of Olig2 function, even attenuated levels of p53 are adequate for biological responses to genotoxic damage.

Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal

“…OLIG2 also appears to directly activate another set of genes, including several core cell cycle regulators, and by this means promotes NS cell proliferation. The contribution of Olig2 to the proliferation of both normal and malignant neural progenitors has been described previously, although this work has focused on OLIG2's antagonism of Cdkn1a (also OLIG2-bound here) and the p53 pathway (Ligon et al 2007;Mehta et al 2011;Sun et al 2011b), rather than the novel functions in directly inducing cell cycle activators and repressing quiescence genes that we describe here. It will be interesting to determine how previously described post-translational mechanisms such as phosphorylation of key residues of OLIG2 (Li et al 2011a;Sun et al 2011b) and interactions with TRP53 protein (Mehta et al 2011) combine with chromatin-level epigenetic and co-factor-mediated mechanisms described here to explain how OLIG2 can be directed toward such context-specific functions to both activate and repress target gene expression.…”

Comparative Expression Analysis Reveals Lineage Relationships between Human and Murine Gliomas and a Dominance of Glial Signatures during Tumor PropagationIn Vitro

“…S8). Pten/Rb tumor grafts strongly express olig2, offering a possible explanation for a selective downregulation of p53 function in the absence of a genetic mutation (51).…”

A frightening thought: Neuronal activity enhances tumor growth

“…These include oligodendrocytes precursor cells (OPCs), which are destined to give rise to the cells that form the insulating myelin sheet around nerve fibers. OPCs are characterized by the expression of the transcription factor Olig-2 that represses the p53 tumor suppression pathway, allowing cells to continue dividing postnatally [2]. Consequently, these Olig-2-expressing cells have a heightened susceptibility to cancers as a result of somatic mutations in oncogenes.…”