Post-translational modifications and activation of p53 by genotoxic stresses

In unstressed cells, the tumor suppressor protein p53 is present in a laten t state and is maintained at low levels through targeted degradation. A var iety of genotoxic stresses initiate signaling pathways that transiently sta bilize the p53 protein, cause it to accumulate in the nucleus, and activate it as a transcription factor. Activation leads either to growth arrest at the G(1)/S or G(2)/M transitions of the cell cycle or to apoptosis. Recent studies point to roles for multiple post-translational modifications in med iating these events in response to genotoxic stresses through several poten tially interacting but distinct pathways. The approximate to 100 amino-acid N-terminal and approximate to 90 amino-acid C-terminal domains are highly modified by post-translational modifications. The N-terminus is heavily pho sphorylated while the C-terminus contains phosphorylated, acetylated and su moylated residues. Antibodies that recognize p53 only when it has been modi fied at specific sites have been developed, and studies with these reagents show that most known post-translational modifications are induced when cel ls are exposed to genotoxic stresses. These recent results, coupled with bi ochemical and genetic studies, suggest that N-terminal phosphorylations are important for stabilizing p53 and are crucial for acetylation of C-termina l sites, which in combination lead to the full p53-mediated response to gen otoxic stresses. Modifications to the C-terminus inhibit the ability of thi s domain to negatively regulate sequence-specific DNA binding; additionally , they modulate the stability, the oligomerization state, the nuclear impor t/export process and the degree of ubiquitination of p53.