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Introduction
The p53 protein was first described in 1979 by several research groups as a cellular factor forming a complex with the simian virus 40 large tumour antigen (1,2). Subsequent studies demonstrated excessive accumulation of p53 both in cells expressing viral tumour antigens and in cancer cells negative for viral infections, whereas p53 levels were low in normal, uninfected cells (3,4). In the early 1980s, p53 was recognised as an oncoprotein whose upregulation by tumour viruses or other mechanisms could contribute to cellular transformation (5,6). Indeed, the TP53 cDNA cloned from various cancer cell lines was shown to immortalise primary cells, induce multilayer cell growth and promote tumourigenicity in animal models, thereby experimentally substantiating the oncogenic role of p53 in tumour development (7,8). In the late 1980s, DNA sequencing of the TP53 gene isolated from tumour cells revealed frequent missense mutations conferring oncogenic features to the mutant p53 proteins (9,10). Conversely, the expression of wild-type p53 in transformed cells was shown to suppress the transformed phenotype without inducing damaging effects in non-transformed cells (11,12). The critical role of p53 as a tumour suppressor was further demonstrated in patients with Li-Fraumeni syndrome, associated with monoallelic germline TP53 mutations and characterized by a high predisposition to various cancer types, including breast cancer, sarcomas, brain tumours, leukaemia and adrenal gland cancers (13,14). The observation that tumours developing in patients with Li-Fraumeni syndrome have lost the wild-type TP53 allele definitively established p53 as a tumour suppressor factor (15).
The scientific evidence accumulated over the past 40 years since the discovery of p53 has shown that this oncosuppressor is involved in regulating a broad range of cellular processes (16,17). These include cell cycle control, activation of DNA repair mechanisms in response to genetic damages, programmed cell death in response to severe cellular stress, induction of cell senescence and regulation of metabolic pathways (Fig. 1) (18,19). Therefore, mutations within the TP53 gene and expression of mutant p53 proteins can be considered to be involved in virtually all hallmarks of cancer (20).
TP53 is the most commonly mutated gene in human cancers, with mutation frequencies exceeding 50% in at least 20 tumour types, including colorectal, ovarian and oesophageal carcinoma and lung cancer (Fig. 2). Certain nucleotide changes in the TP53 gene...