Expression of Mutant p53 Proteins Implicates a Lineage Relationship between Neural Stem Cells and Malignant Astrocytic Glioma in a Murine Model

Abstract

SUMMARY Recent studies have identified genes and core pathways that are altered in human glioblastoma. However, the mechanisms by which alterations of these glioblastoma genes singly and cooperatively transform brain cells remain poorly understood. Further, the cell-of-origin of glioblastoma is largely elusive. By targeting a p53 in-frame deletion mutation to the brain, we show that p53 deficiency provides no significant growth advantage to adult brain cells, but appears to induce pleiotropic accumulation of cooperative oncogenic alterations driving gliomagenesis. Our data show that accumulation of a detectable level of mutant p53 proteins occurs first in neural stem cells in the subventricular zone (SVZ) and that subsequent expansion of mutant p53-expressing Olig2+ transit-amplifying progenitor-like cells in the SVZ-associated areas initiates glioma formation. SIGNIFICANCE Glioblastoma is the most malignant form of astrocytic gliomas and the most common primary brain cancer in adults. The poor prognosis of glioblastoma emphasizes the urgent need for a greater understanding of disease pathogenesis. We demonstrate that p53 deficiency can cooperate with diverse mitogenic signaling pathways to induce malignant glioma. For example, inactivation of the Nf1 tumor suppressor, activation of mitogen-activated protein kinase, or activation of phosphatidylinositol-3-OH kinase pathways are not essential, but can promote p53-mediated glioma formation. Furthermore, expression of mutant p53 proteins is identified as a marker for glioma cells in all stages. Analysis of brain cells with a detectable level of mutant p53 expression provides important insights into the role of neural stem cells and transit-amplifying progenitors in p53-mediated gliomagenesis.

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

“…Furthermore, in accordance with the reported role of p53 in suppressing transformation of NPCs (18)(19)(20)(21)(22), ETCimpaired/p53-deficient NPCs grow faster upon oncogenic activation and are capable of forming brain tumors in a subset of orthotopically transplanted animals. The incomplete penetrance observed in these experiments may be due to the fact that other cooperative oncogenic events may have to be acquired, as previously suggested (21), and indeed these might be favored by ROS increase as well as by p53 loss. Genome stability could also be affected via metabolic stress-dependent inhibition of metabolism-sensitive DNA repair enzymes, such as poly(ADP-ribose) polymerase (33), or indirectly via iron/sulfur (Fe/S) cluster formation (34-37) as part of a mitochondrial retrograde signaling.…”

“…Finally, p53, which has emerged as an important regulator of mitochondrial metabolism and cellular redox control (15)(16)(17), is often found mutated or functionally inactivated in HGG. Its inactivation in neural progenitor/stem cells (NPCs), which act as HGG cells of origin, contributes to gliomagenesis (18)(19)(20)(21)(22). In particular, deletion of a significant portion of the p53 DNA binding domain induces the accumulation of cooperative oncogenic events, thus leading to HGG (21).…”

“…Its inactivation in neural progenitor/stem cells (NPCs), which act as HGG cells of origin, contributes to gliomagenesis (18)(19)(20)(21)(22). In particular, deletion of a significant portion of the p53 DNA binding domain induces the accumulation of cooperative oncogenic events, thus leading to HGG (21). However, it remains to be determined whether p53 metabolic functions contribute to suppression of neoplastic transformation in the nervous system.…”

Oncogenes and Tumor Suppressor Genes

“…Reactivation of p53 by pharmacological intervention restores asymmetric cell division (Cicalese et al 2009). In a separate model, expression of the exon-5-6-less TP53 allele in neural stem cells was followed by the expansion of transient-amplifying progenitorlike cells and subsequent development of malignant astrocytic glioma (Wang et al 2009b). These studies indicate a role of p53 in the regulation of stem cell division in addition to its well-documented role in transformation.…”

“…Different mutant TP53 alleles, including null and internally truncated alleles, are generated, which can result in different phenotype. Indeed, mutant but not null mutation promotes expansion of neuronal progenitor cells and subsequent astrocytic glioma formation (Wang et al 2009b). Cre transgenes under the control of various different promoters have been used for the conditional inactivation of Brca1.…”