p53 Isoforms as Modifiers of the p53-Dependent Responses: A Hidden Code?

The tumor suppressor protein p53, encoded by the TP53 gene, is known as the “Guardian of the Genome”, and alterations in TP53 are common to more than 50% of human cancers. p53 is a critical regulator of cellular responses to several stress conditions, such as DNA damage, oncogene activation, and nutrient starvation. p53 was traditionally described as a single transcription factor; however, now it is recognized as a complex family of isoforms generated through alternative promoter usage, alternative splicing, and alternative initiation of translation. These processes give rise to at least 12 distinct p53 isoforms in humans, including p53α (the canonical full-length isoform), p53β, p53γ, Δ40p53, Δ133p53, and Δ160p53, each with unique structural and functional properties. p53 isoforms differ in the presence or absence of specific and fundamental domains located both at N- and C-terminal ends, determining an altered DNA-binding potential, transcriptional activity, and protein–protein interactions. For instance, Δ133p53 isoforms lack part of the N-terminal domains and can exert dominant-negative effects over full-length p53α or modulate alternative transcriptional programs. Similarly, p53β and p53γ isoforms, which have a unique C-termini, influence cellular senescence. The expression patterns of p53 isoforms are tissue-specific and dynamically regulated under both physiological as well as pathological conditions. Alterations of isoform balance have been involved in tumor progression, metastasis, and therapy resistance. Importantly, specific isoforms can either enhance or limit canonical p53 tumor suppressor functions, thereby contributing to the functional diversity of the p53 network. Overall, the p53 isoform landscape adds a critical layer of complexity to p53 biology. In this review, we summarize the mechanisms underlying the production of p53 isoforms, their functions, and their expression in cancer, with the idea that a better understanding of the differential regulation and functional interplay of p53 isoforms may provide novel biomarkers and therapeutic targets in cancer.