Cerebellum Development and Tumorigenesis: A p53-Centric Perspective

The p53 protein has been extensively studied for its role in suppressing tumorigenesis, in part through surveillance and maintenance of genomic stability. p53 has been associated with the induction of a variety of cellular outcomes including cell cycle arrest, senescence, and apoptosis. This occurs primarily, but not exclusively, through transcriptional activation of specific target genes. By contrast, the participation of p53 in normal developmental processes has been largely understudied. This review focuses on possible functions of p53 in cerebellar development. It can be argued that a better understanding of such mechanisms will provide needed insight into the genesis of certain embryonic cancers including medulloblastomas, and thus lead to more effective therapies. Numerous mouse models of medulloblastoma depend on p53 ablation. However, most cases of the human disease are not associated with mutation(s) in p53. This raises the question of the role of p53 during the genesis of medulloblastomas.Altering the dosage of the negative regulators of p53 (Mdm2 and Mdm4) in vivo has resulted in impaired cerebellar development in mice.p53 can downregulate Hedgehog signaling output through the negative regulation of Gli proteins. This results in decreased proliferation of Sonic Hedgehog (Shh)-sensitive cells.Activated Hedgehog signaling can lead to the inhibition of p53 activity through Mdm2-dependent proteasomal degradation. This in turn increases the activation of the Shh pathway and proliferation in Shh-sensitive cells.Mouse models simultaneously deficient in key effectors of the DNA repair pathway (such as Lig4, Xrcc4, or Brca2) and p53 show early and strong induction of medulloblastoma with 100% penetrance. This reinforces the important role for DNA damage repair mechanisms and possible cooperation with the p53 pathway during cerebellar development.