Massively regulated genes: the example of TP53.

Intensive study of the TP53 gene over the last three decades has revealed a highly complex network of factors that regulate its performance. The gene has several promoters, alternative splicing occurs and there are alternative translation initiation sites. Up to 10 p53 isoforms have been identified. At the post-translational level, p53 activity depends on its quantity in the cell and on qualitative changes in its structure, intracellular localization, DNA-binding activity and interactions with other proteins. Both accumulation and activation are regulated by an intricate pattern of post-translational modifications, including phosphorylation, acetylation, ubiquitination, sumoylation, neddylation, methylation and glycosylation. The Mdm2 protein, a negative regulator of p53, is the most important determinant of p53 abundance and subcellular localization. Enzymes that post-translationally modify p53 by phosphorylation, methylation and acetylation fine-tune p53 binding to recognition sequences in DNA and p53 interactions with transcription cofactors at promoters of target genes, thereby exerting a discriminatory role in p53 function. This multitude of parameters determining expression, modification, accumulation and localization of p53 proteins may explain how a single gene can display an extensive repertoire of activities. Presumably this is needed, because the p53 protein can have such profound consequences for a cell.