The TP53 tumor suppressor gene: From molecular biology to clinical investigations

Extensively studied over the past four decades, the TP53 gene has emerged as a pivotal watchman in cellular defense and a key factor in cancer biology. TP53 is the most frequently mutated gene in human malignancies, 50% of which carry alterations to it. Initially, the functions of p53 were thought to be restricted to cell-cycle arrest and apoptosis. With time, however, a growing number of functions have been discovered, illustrating p53's role as a master switch between any cellular stress and cellular or multicellular responses that contribute to its anti-tumor activity. Indeed, the peculiar landscape of TP53 mutations and its high heterogeneity are linked both to the structure of the protein and its ubiquitous function in regulating cellular homeostasis. Mutations in p53 are associated with poor response to therapy and shorter survival in most cancer types, and the diagnosis of p53 mutations is currently used to improve case management in some types of leukemia and lymphoma. Although TP53 has been defined as a tumor suppressor gene, overexpressed mutated p53 variants found in human tumors are defined as dominant oncogenes with a potential gain of function, which makes the gene a very attractive target for developing new cancer treatments. Beyond its role in cancer, our review also highlights TP53's significance in non-neoplastic conditions, such as bone marrow failure syndromes and certain developmental disorders, where chronic p53 activation plays a crucial role in cellular stress responses, demonstrating its broader biological importance.