Somatic mutations in p53, which inactivate the tumour-suppressor function of p53 and often confer oncogenic gain-of-function properties, are very common in cancer1,2. Here we studied the effects of hotspot gain-of-function mutations in Trp53 (the gene that encodes p53 in mice) in mouse models of WNT-driven intestinal cancer caused by Csnk1a1 deletion3,4 or ApcMin mutation5. Cancer in these models is known to be facilitated by loss of p533,6. We found that mutant versions of p53 had contrasting effects in different segments of the gut: in the distal gut, mutant p53 had the expected oncogenic effect; however, in the proximal gut and in tumour organoids it had a pronounced tumour-suppressive effect. In the tumour-suppressive mode, mutant p53 eliminated dysplasia and tumorigenesis in Csnk1a1-deficient and ApcMin/+ mice, and promoted normal growth and differentiation of tumour organoids derived from these mice. In these settings, mutant p53 was more effective than wild-type p53 at inhibiting tumour formation. Mechanistically, the tumour-suppressive effects of mutant p53 were driven by disruption of the WNT pathway, through preventing the binding of TCF4 to chromatin. Notably, this tumour-suppressive effect was completely abolished by the gut microbiome. Moreover, a single metabolite derived from the gut microbiota—gallic acid—could reproduce the entire effect of the microbiome. Supplementing gut-sterilized p53-mutant mice and p53-mutant organoids with gallic acid reinstated the TCF4–chromatin interaction and the hyperactivation of WNT, thus conferring a malignant phenotype to the organoids and throughout the gut. Our study demonstrates the substantial plasticity of a cancer mutation and highlights the role of the microenvironment in determining its functional outcome.
GoodGuyDrew on August 1st, 2020 at 16:51 UTC »
Although this work is interesting, the primary mechanisms by which mutant p53 promotes tumorigenesis are likely loss-of-function and the dominant-negative effect, whereby mutant p53 interferes with the function of wild-type or “normal” p53 (one of the most important tumor suppressor genes in the human genome).
Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation
https://pubmed.ncbi.nlm.nih.gov/2040013/
A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies
https://pubmed.ncbi.nlm.nih.gov/31395785/
There have been A LOT of articles which suggest that mutant p53 has other functions, termed “gain-of-function”. But it seems that with every new article, a different molecular function is found.
In my view this is the result of publication bias. If you find something that has been found before, it’s viewed as less interesting and gets published in a lower-tier journal. If you find something new, it’s viewed as exciting and gets published in Nature.
The findings of this study may be real and reproducible, but when it comes to the big question of: “How does p53 mutation cause cancer in humans?” The answer is not likely “Something no-one has ever seen in 40 years of studying p53”. But rather “Through loss-of-function and the dominant-negative effect.”
End rant.
Chel_of_the_sea on August 1st, 2020 at 15:56 UTC »
EDIT: This post was briefly taken down, then edited without my involvement or any explanation given. Moderators do not, as far as I know, have the power to do so, and I did not edit the portion in question myself. I mentioned this in the comments below, which have now been outright deleted without explanation (apparently by the sub mods, according to my user page), along with the entire thread below them. See my user page for the deleted content.
EDIT2: The mods here claim, in another thread, that neither they nor admins have the unilateral power to do so. Their claim is that this was a failed edit that silently 'didn't take'. I've never encountered this before and am skeptical, but want to present the full story.
ELI5:
p53 is a tumor-suppressing gene. That means that it's involved in repairing damage to DNA, and in causing cells with damaged DNA to self-destruct (a process called apoptosis). This is important because accumulated DNA damage is how cells can become cancerous: basically, you have to damage all the different parts of the DNA that are supposed to stop them from doing that. By knocking out p53 and other tumor-suppressing genes, you remove a major defense mechanism against cancer.
This paper claims that the gut microbiome - the accumulated blob of bacteria that live inside your digestive tract and, among other things, assist digestion and stop more hostile bacteria from moving in - can under some circumstances modify the effect of the p53 gene. It goes on to claim that the modified p53 gene is not only not stopping cancer, but is in fact oncogenic (cancer-causing) in its own right.
Finally, the paper claims that the effect of gut bacteria can be duplicated by applying a single chemical to (mouse) cells. This suggests, but doesn't prove, that this chemical is the means by which the bacteria of the gut microbiome can cause p53 to mutate [edit: cause the mutated p53 to start causing, rather than preventing, cancer - the microbiome doesn't trigger the mutation itself].
PopeyesChickenNotKFC on August 1st, 2020 at 15:43 UTC »
Can someone explain like I am 5