p53 in the CNS: Perspectives on Development, Stem Cells, and Cancer

Abstract

The p53 tumor suppressor potently limits the growth of immature and mature neurons under conditions of cellular stress. Although loss of p53 function contributes to the pathogenesis of central nervous system (CNS) tumors, excessive p53 function is implicated in neural tube defects, embryonic lethality, and neuronal degeneration. Thus, p53 function must be tightly controlled. The anti-proliferative properties of p53 are mediated, in part, through the induction of apoptosis, cell cycle arrest, and senescence. Although there is still much to be learned about the role of p53 in these processes, recent evidence supports exciting new roles for p53 in a wide range of processes, including neural precursor cell self-renewal, differentiation, and cell fate decisions. Understanding the full repertoire of p53 function in CNS development and tumorigenesis may provide us with novel points of therapeutic intervention for human diseases of the CNS.

Keywords: MDM2; MDM4; apoptosis; birth defects; cancer stem cell; glioblastoma; medulloblastoma; nervous system; neural stem cell; p53.

Figure 1.

The level of p53 as a determinant of life and death. Elevating basal p53 function beyond its normal wild-type level can enhance tumor suppression. However, as p53 levels continue to rise, the benefits of enhanced tumor suppression become increasingly negated by the deleterious effects of the antigrowth properties of p53 in developing and homeostatic tissues. Chronic or aberrantly elevated p53 function is implicated in the neurodegeneration associated with several central nervous system pathologies, including Alzheimer and Parkinson diseases in adults and congenital birth defects and lethality in developing embryos. Conversely, loss of p53 function increases lifelong susceptibility to cancer and may abrogate a critical developmental checkpoint in the embryo.