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Gain-of-function mutant p53: history and speculation
Jill Bargonetti 1,* and Carol Prives 2,*
1 Department of Biological Sciences Hunter College and The Graduate Center, City University of New York, New York, NY 10021, USA
2 Department of Biological Sciences, Columbia University, New York, NY 10027, USA
*Correspondence to:Jill Bargonetti, E-mail: Bargonetti@genectr.hunter.cuny.edu; Carol Prives, E-mail: clp3@columbia.edu
J Mol Cell Biol, Volume 11, Issue 7, July 2019, Pages 605-609  https://doi.org/10.1093/jmcb/mjz067
Keyword: mutation amino acids cancer chromatin dna dna repair dna replication genes tp53 gene tumor suppressor genes missense mutation oncogenes protein p53 mice transcription factor transcriptional activation
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 Levine and Oren, 2009). 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 (Baker et al., 1989). 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 (Eliyahu et al., 1989; Finlay et al., 1989). 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 (Lu, 2017; Lane and Verma, 2019).