The history of the p53 tumor suppressor (and of the p53 field of research) is quite extraordinary. First discovered in the late 1970s as a protein associated with the SV40 large tumor antigen (and also as a protein that was found in some non-virally transformed cells), p53 was commonly viewed as a facilitator of oncogenic cell transformation (for an excellent review of the early history of p53 see . It took nearly 10?years for the cancer research field to realize that wild-type p53 is a tumor suppressor protein. It started in 1989, when Vogelstein and colleagues discovered that deletions, insertions, and point mutations in the TP53 gene were key signatures of colorectal carcinoma (. This was supported by the demonstration that wild-type p53 cloned from non-transformed cells was capable of suppressing the ability of oncogenes to transform cells (; . Soon thereafter, a flurry of studies including human cancer genetics, mouse models, and cell biology cemented the identity of p53 as a major tumor suppressor. It is now well established that TP53 is mutated with high frequency in more cancers than any other tumor suppressor gene. In fact, the TP53 gene and its protein product(s) are the most well scrutinized entities in cancer biology. For example, at the time of writing this essay, there are 95547 entries in PubMed that have p53 in the title or abstract. International conferences that focus solely on p53, or on mutant p53, or on Mdm2 (the negative regulator of p53), or even on p53 isoforms are held with impressive regularity and are attended by literally hundreds of researchers (; . Central to the p53 story have been the continuous and seminal contributions from Arnold Levine and his trainees, many of whom have gone on to populate the p53 field themselves. The list of critical discoveries that emanated from the Levine lab is long. To name but a few, Levine and colleagues were among the discovers of the protein itself (, were the first successful cloners of the p53 gene (, were the first to demonstrate that the wild-type form of the protein suppresses oncogenic transformation (, and the Levine lab identified Mdm2 as a p53 binding partner that inhibits the function of p53 (. More recently, they have populated the bioinformatics field leading to computational studies that have provided global insights into p53, Mdm2, and their roles in cancer. The discovery that p53 genes isolated from non-transformed normal diploid cells were able to suppress cell transformation posed a dilemma. How was it possible to reconcile earlier findings supporting a pro-oncogenic role for p53? Here too Levine’s group provided the basis for understanding how this quandary could be solved. The changes in TP53 that are found most often in human cancers are called the ‘hot spot’ mutations; these are missense mutations located in the p53 DNA binding domain (reviewed in . Highly frequent hot spot missense mutations are a key feature of gain-of-function (GOF) oncogenes, while the mutation spectrum of loss-of-function tumor suppressors usually consists of more varied mutation types distributed evenly across the inactivated gene (. This implies that p53 mutation might simply abrogate the wild-type function(s) of the protein, while the hot spot mutants might have gained additional novel oncogenic activities. The GOF hot spot missense mutations for p53 have a loss of sequence-specific DNA binding (; , but they also have characteristics of oncogenes as will be discussed later. These missense p53 hot spot mutations are coupled with the protein retaining all other functional domains (see . The Levine team showed that mutations in p53 that activate the ability of p53 to transform cells also increase the half-life of the altered variants (. This finding helped to explain the high levels of oncogenic mutant p53 (mtp53) found in human cancers (. The Levine group identified a gained function for p53 by first showing that mtp53 proteins help to transform wild-type p53-expressing cells to become tumorigenic (, . Figure 1 Domain organization of the p53 protein. The domain boundaries corresponding to human p53 protein are shown with amino acid numbers at bottom. The red outlined boxes show transcription activation domains 1 and 2 (AD1, AD2); the brown outlined box indicates the PR domain; the purple outlined box corresponds to the site-specific DNA binding domain; the non-specific DNA binding carboxyl terminal region comprises the green outlined box that indicates the OD followed by the yellow outlined box containing the lysine-rich 6?K region (CTD). The full sequence of the CTD is shown with the six lysine residues in red and listed below. The GOF missense mutations at R175, R248, and R273 are indicated on top of the purple outlined site-specific DNA binding domain. Listed below are some of the key functions that AD1 and AD2 on the left and CTD on the right are known to promote. Figure 1 Domain organization of the p53 protein. The domain boundaries correspondi
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