The TP53 gene contains a diversity box that makes it more than a tumor suppressor

The p53 protein is a transcription factor that is most commonly known and studied as a tumor suppressor preventing cancers. At least 50% of cancers have TP53 mutations that inactivate p53 functions and many other cancers utilize physiological means to inactivate p53 tumor suppressor functions, pointing to the fundamental role of p53 as a barrier to the expansion of transformed cells. An intriguing characteristic of the TP53 gene is the presence of multiple regulatory structures that control the diversity of p53 expression within a short region of 1200 bp between exon 2 and exon 5. This "diversity box" encompasses a dense array of regulatory signals that control the selective activation and cell-fate specificity of p53 suppressor functions. These signals include multiple post-translational modification sites and motifs regulating the expression of N-terminally truncated p53 isoforms Δ40p53α and Δ133p53α, all of which contribute to modulate p53 functions and phenotypes. These functions may play a role in early development, DNA repair, wound healing versus cell death, as well as enhanced metabolic and mitochondrial functions, reversal of cellular senescence, cell-type- specific functions, communication with the immune system, and even accelerated aging. Remarkably, the TP53 diversity box harbors several frequent polymorphisms known to modulate p53 functions, which are in linkage disequilibrium and specify unique haplotypes that differ from one population to another. This suggests that genetic variations in the diversity box may contribute to differences in epidemiological and pathological traits of the same cancer types among individuals from different ancestries.