title: Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme.
abstract: Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a uniformly poor prognosis. Despite decades of research on the topic, limited progress has been made to improve the poor survival associated with this disease. GBM arises de novo (primary GBM) or via dedifferentiation of lower grade glioma (secondary GBM). While distinct mutations are predominant in each subtype, alterations of tumor suppressor p53 are the most common, seen in 25-30 % of primary GBM and 60-70 % of secondary GBM. Various roles of p53 that protect against neoplastic transformation include modulation of cell cycle, DNA repair, apoptosis, senescence, angiogenesis, and metabolism, resulting in an extremely complex signaling network. Mutations of p53 in GBM are most common in the DNA-binding domain, namely within six hotspot mutation sites (codons 175, 245, 248, 249, 273, and 282). These alterations generally result in loss-of-function, gain-of-function, and dominant-negative mutational effects for p53, however, the distinct effect of these mutation types in GBM pathogenesis remain unclear. Signaling alterations downstream from p53 (e.g., MDM2, MDM4, INK4/ARF), p53 isoforms (e.g., p63, p73), and microRNAs (e.g., miR-34) also play critical roles in modulating the p53 pathway. Despite novel mouse models of GBM showing that p53 combined with other mutation generate tumors de novo, the role of p53 as a molecular marker of GBM remains controversial with most studies failing to show an association with prognosis. Regarding treatment in GBM, p53 targeted-gene therapy and vaccinations have reached phase I clinical trials while therapeutic drugs are still in preclinical development. This review aims to discuss the most recent findings regarding the impact of p53 mutations on GBM pathogenesis, prognosis, and treatment.
authors.affiliation: Department of Neurosurgery, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Bryant
authors.initials: B
authors.lastname: England
authors.forename: Tiangui
authors.initials: T
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Karsy
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D051379:Mice; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53