Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
Disease
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Query: UNIPROT:P04637 (
p53
)
77,613
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Somatic mutations in
p53
, which inactivate the tumour-suppressor function of
p53
and often confer oncogenic gain-of-function properties, are very common in cancer
1,2
. 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 deletion
3,4
or Apc
Min
mutation
5
. Cancer in these models is known to be facilitated by loss of
p53
3,6
. 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 Apc
Min/+
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.
...
PMID:The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic. 3294 62
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