Questions regarding p53 and cancer

Q 1: Because p53 and its related genes are transcription factors, meaning that they are regulatory genes whose products control the expression of other genes, changes in these genes have cascading consequences. Why is this?
A: By changing these genes, there is less protection from the development of cancer. The p53 protein is activated in order to stop the repair of damaged cells which could contain mutations. The protein helps to initiate apoptosis so that the damaged/mutated cells will die. If the p53 protein is altered or inactive, there is no restriction on abnormal cell growth. Thus, cancer development becomes very possible.

Q 2: In an evolutionary sense, why is it informative to study cancer and its implications in mice (see Lee and Bernstein, 1993 and Bourdon, 2007)?
A: Cancer development between humans and mice is quite similar. The p53 gene is orthologous in humans and mice, serving as a checkpoint during cell proliferation. The p53 gene commonly has mutations or "rearrangements." Since p53 is a tumor suppressor gene, then any mutations in it would cause cancer in both humans and in mice. Researchers use mice to test these assumptions, since the results are quite applicable to humans, and much easier to examine. The evolutionary effects of p53 alterations cause dramatic results for the mice, thus providing informative data for us to interpret.

Q 3: Bourdon discusses the sequence similarity in portions of p53, p63 and p73, and refers to them as a gene family. How do you think these genes arose? Are they paralogs or orthologs of one another? By what mechanism might they have gained new functions?
A: The p53, p63, and p73 gene family are paralogs of one another. This is because they are structurally the same, indicating a similar ancestral gene, but have diverged in function. This can happen through mechanisms like mutation and selection after gene duplication in a species. If an organism had a duplication, the gene would be free to mutate, leading to new genes within the species.

Q 4: In the Bourdon paper, the author discusses how changes in expression of the 9 different p53 isoforms (proteins) can cause “genome instability, cancer and other pathologies.” Why then is it important to study protein folding and mis-folding in these isoforms?
A: It is important to study protein folding and mis-folding in these proteins because by understanding them we can better develop treatments for cancer and other pathologies caused by changes in their expression. By studying their mis-folding, it will help us understand their role when they are correctly expressed. The p53 gene is mutated in 60% of cancers so understanding all of the isoforms will contribute to an understanding of p53 as a whole. A better understanding of the isoforms and their role in p53 expression could also bring us closer to cancer therapies because we may be able to further narrow down specifically which isoforms lead to incorrect folding or expression in the p53 gene.

Q 5: Typically, p53 is a “tumor-suppressor gene,” which indicates that if it loses function, tumors will result. However, expression of some of the isoforms of p53 can actually contribute to tumor formation. Further, not all mutations in p53 result in a loss of function. This makes it difficult to understand the clinical role of p53. Considering people like Debbie, why is it so vital to determine the status of p53 in each patient?
A: Determining the status of p53 in a patient is very important because it can reveal very important things about the patient. If there are mutations in p53, this patient may be resistant to radiation, which will be important in treatment. If p53 is completely missing, this could suggest a tumor’s cause to doctors. Also, since some of the p53 mutations and isoforms gain transcription abilities and others do not, this may be a clue to which are in a particular patient’s tumors. As mentioned in the Bourdon article, p53 affects a great deal of processes in the body, not just suppression of tumors. If p53 is mutated, there may be things to deal with as well as the cancer. This information will give the doctor a better idea of what he/she is dealing with. Even though the research is currently inconclusive about which p53s do exactly what, knowing what is going on within the body will help both doctors and future researchers.