Signaling to p53: breaking the posttranslational modification code

In unstressed cells, the tumor suppressor protein p53, a tetrameric transcr iption factor, is present in a latent state and is maintained at low levels through targeted degradation. A variety of cellular stresses including DNA damage, hypoxia, nucleotide depletion, viral infection, and cytokine-activ ated signaling pathways that transiently stabilize the p53 protein, cause i t 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 transition s of the cell cycle or to apoptosis. The molecular mechanisms by which stab ilization and activation occur are incompletely understood, but accumulatin g evidence points to roles for multiple posttranslational modifications in mediating these events through several potentially interacting but distinct pathways. Both the similar to 100 amino acid N-terminal and similar to 90 amino acid C-terminal domains are highly modified by phosphorylation and ac etylation, whereas modifications to the central sequence-specific DNA bindi ng domain have not been reported. Seven serines and one threonine in the fi rst 46 residues of the transactivation domain and four to five serines in t he carboxyl-terminal domain are now known to be phosphorylated, and Lys320 and Lys382 in the carboxyl-terminal domain (human p53) can be acetylated. A ntibodies that recognize p53 only when it has been modified at specific sit es have been developed by several laboratories, and studies with these have shown that most of the known posttranslational modifications are induced w hen cells are exposed to DNA-damaging agents. Exceptions are Ser378, which is reported to be constitutively phosphorylated, and Ser376, which is depho sphorylated in response to DNA damage. These recent results, coupled with b iochemical and genetic studies, suggest that several amino-terminal phospho rylations can be important in stabilizing p53 in response to DNA damage and in directing acetylation at C-terminal sites. DNA damage-induced modificat ions to the C-terminus inhibit the ability of this domain to negatively reg ulate sequence-specific DNA binding either by inducing a conformational cha nge in the protein or by inhibiting non-sequence-specific DNA binding by th e C-terminus. C-terminal modifications also modulate the oligomerization st ate of p53, and may modulate nuclear import/export. Modifications in respon se to DNA damage to other components that interact with p53 may also be imp ortant. In most cases, clear roles for specific modifications, interactions among individual modifications, and the enzymes responsible for each modif ication remain to be defined. Nevertheless, the field appears poised for ma jor advances in the understanding of the molecular mechanisms that regulate p53 function. (C) 2000 Editions scientifiques et medicales Elsevier SAS.