Author details

TP53 encodes a transcription factor named p53, which has only 393 amino acids. It functions as a tetramer of two dimers, each binding a sequence RRRCWWGYYY (R = A/G, W = A/T, Y = C/ T). When a gene contains two such sequences separated by 0–13 base pairs, it becomes a potential target of p53. Up to date, out of 30,000 human genes known so far, 3661 have been found to contain such p53 response elements. In another word, more than 10% of our entire genome is possibly under p53 regulation. Among these target candidates, 346 have been confirmed to be bound and regulated by p53, including 246 upregulated by p53, 91 downregulated by p53, and nine can go either way [31]. That is to say, p53 has the power to

Normally, after translation, p53 is degraded rapidly through ubiquitination by MDM2, an E3 ubiquitin ligase that happens to be a true target gene of p53. In another word, p53 is a well selfdisciplined molecule and can take good care of itself and would not allow itself to accumulate unnecessarily. In response to cellular stresses like DNA damage, oncogene activation, or hypoxia, however, p53 dissociates from MDM2 through various protein modifications such as phosphorylation, acetylation, or methylation, becoming an active transcription factor. Then, p53 rolls out a transcriptional program, namely activating certain genes and/or suppressing some others, to cause cell cycle arrest, senescence, or apoptosis, thereby managing the cellular crisis and bringing the microenvironment back to normal. For this reason, p53 has earned the honor as the "guardian of the genome," and also for this reason, a cell must depower p53 first

There are several ways to depower p53 in a cell. Gene mutation is the first one. As mentioned earlier, more than 50% of cancers have TP53 mutations. Interestingly, a majority of these mutations (~ 90%) are missense. In another word, the mutated gene can still be transcribed into a protein product, just different from the wild-type p53. Furthermore, most of these mutations take place at ~190 codons, which encoding the amino acid residues 102–292 within the DNA-binding domain of the transcription factor. Some of the mutant p53 protein products still possess DNA-binding capability to a degree, just weaker, about 0–75% of the wild-type p53 depending on the exact location of the mutation. This is also believed to be the reason for different cancerous phenotypes. Environmental carcinogens tend to cause selective mutations within TP53 and thereby lead to tissue-specific cancers. For instance, tobacco smoke (carcinogen: benzoapyrene diol epoxide) tends to induce mutations at G245 V, G245C, and R249M, which are commonly seen in association with ESCC patients [32]. In vitro studies have demonstrated that the expression of mutant p53 in normal cells with TP53 deletion gives them new properties like rapid proliferation, loss of contact inhibition, accelerated migration/invasion, and tumorigenic potential in nude mice, which are the properties that a cancer cell usually

possesses, further indicating TP53 mutations in favor of cancer development.

Compared to gene mutation, posttranscriptional regulations also play a significant role in depowering p53. As discussed earlier, p53 protein is constantly degraded by MDM2-mediated ubiquitination. MDM4, a homolog of MDM2, can suppress p53 activation as well, and so do several others, like SIRT1, YY1, MTA2, and HDAC1. Cancer cells learn to cast curses on p53 by overexpressing these proteins in case TP53 mutation did not work. The expression of microRNAs is another example. Several species of microRNAs (i.e., miR-125b, miR-504, and

shut a gene down or open it up, "all up to its mood."

in order to become malignant.

6 Esophageal Cancer and Beyond

Jianyuan Chai1,2\*

