Abstract
p53 is one of the most intensively studied tumor suppressors. It transcriptionally regulates a broad range of genes to modulate a series of cellular events, including DNA damage repair, cell cycle arrest, senescence, apoptosis, ferroptosis, autophagy, and metabolic remodeling, which are fundamental for both development and cancer. This review discusses the role of p53 in brain development, neural stem cell regulation and the mechanisms of inactivating p53 in gliomas. p53 null or p53 mutant mice show female biased exencephaly, potentially due to X chromosome inactivation failure and/or hormone-related gene expression. Oxidative cellular status, increased PI3K/Akt signaling, elevated ID1, and metabolism are all implicated in p53-loss induced neurogenesis. However, p53 has also been shown to promote neuronal differentiation. In addition, p53 mutations are frequently identified in brain tumors, especially glioblastomas. Mechanisms underlying p53 inactivation in brain tumor cells include disruption of p53 protein stability, gene expression and transactivation potential as well as p53 gene loss or mutation. Loss of p53 function and gain-of-function of mutant p53 are both implicated in brain development and tumor genesis. Further understanding of the role of p53 in the brain may provide therapeutic insights for brain developmental syndromes and cancer.
Highlights
Over 40 years ago, a ~53-kDa protein was detected with high expression levels in cancer cells [1,2,3], igniting the explosive field of p53 research
The tumor suppression function of p53 is fundamentally linked to a variety of central cellular events such as DNA damage repair, cell cycle arrest, apoptosis, senescence, autophagy, ferroptosis, and metabolism, mainly through transcriptional regulation of p53 target genes [7,8]
P53 level is maintained low due to ubiquitination and protein degradation mediated by E3-ubiquitin ligase such as MDM2 [10]
Summary
Over 40 years ago, a ~53-kDa protein was detected with high expression levels in cancer cells [1,2,3], igniting the explosive field of p53 research. Research articles that cited previously reviewed major studies of p53’s roles development, neural stem cell, brain tumor and brain cancer.
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