As we age, our DNA naturally acquires changes, or mutations, due to a mixture of environmental factors and internal cellular errors. Some mutations are inconsequential; however, some are much more detrimental and can cause diseases such as cancer. As our life expectancy increases, our cells have more time to gain these mutations, and this increases the prevalence of these diseases in our population.
Our bodies have inherent mechanisms to detect damaged cells and thereby prevent unhealthy cells from dividing. One such mechanism is through so-called “tumor suppressor proteins” that regulate cell growth and replication by performing checks on the cells as they go through the cell cycle. Damaged cells can have their DNA repaired, or in some cases, the unhealthy cell can be triggered to commit cell suicide. One of the most well-known tumor suppressor proteins is TP53.
In this review, we will discuss the discovery of TP53 and its role in preventing cancer. We will also focus on the role of mutant TP53 in cancer, an aspect that is unique for a tumor suppressor protein.
Discovery of tumor suppressor genes
Until the late 1970s, tumor suppressor genes (TSGs) were considered to be an unproven hypothesis. Knudson used the two-hit hypothesis to explain the hereditary nature of the Retinoblastoma protein (RB) in 1971 [1] (the theory that both copies of the gene need to be inactive to cause disease). However, it took until 1986 for this gene to be recognized as a TSG [2]. Throughout the 70s and early 80s, oncogenes became the prevailing theory as to the molecular cause of cancer, with more and more of these tumor activating genes, such as MYC, RAS, and SRC, being described. It was not until 1985 that the term “tumor suppressor gene” was used for the first time, and not until the early 90s when it became common practice to use TSG instead of the more commonly used term “anti-oncogene”.
TP53 was the second TSG to be named after RB. However, the pathway to discovery was complex for TP53 because it was initially reported in 1979 to be an oncogene by six independent groups [3] (Fig. 1).
