Editing P53 (section)

== Mutations ==
Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional effects.<ref name="Bullock_1997" />
[[File:P53 mutant.jpg|thumb|Pathogenic mechanisms associated with p53 mutations<ref name=ab>{{cite journal | vauthors = Butera A, Amelio I | title = Deciphering the significance of p53 mutant proteins | journal = Trends in Cell Biology | date = July 2024 | volume = 35 | issue = 3 | pages = 258–268 | pmid = 38960851 | doi = 10.1016/j.tcb.2024.06.003 | doi-access = free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref> (A) The wild-type response of p53 involves the formation of homotetramers, which regulate gene expression at p53 responsive elements. (B) In contrast, the dominant-negative effect of p53 mutants occurs through the formation of heterotetramers. These heterotetramers, composed of both p53 wild-type and p53 mutant monomers, lack transcriptional ability. This dominant- negative mechanism can manifest in conditions of heterozygosity, where a p53 wild-type allele coexists with a p53 mutant allele (p53mut/+). (C) Loss- of-function is characterized by the absence of p53 wild-type expression and the lack of any form of activity by the p53 mutant protein. This typically occurs when all p53 alleles are inactivated. (D) Gain-of-function involves the acquisition of neomorphic activities by p53 mutant proteins. These neomorphic activities are often described as the hijacking of additional transcriptional factors, indirectly influencing gene regulation and resulting in pro-tumorigenic phenotypes. Abbreviation: WT, wild type.<ref name=ab/>]]
The large spectrum of cancer phenotypes due to mutations in the ''TP53'' gene is also supported by the fact that different [[protein isoform|isoforms]] of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in ''TP53'' can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recent studies show that p53 isoforms are differentially expressed in different human tissues, and the [[mutation|loss-of-function or gain-of-function mutations]] within the isoforms can cause tissue-specific cancer or provide cancer [[stem cell]] [[cell potency|potential]] in different tissues.<ref name="Bourdon" /><ref name="pmid21779513">{{cite journal | vauthors = Khoury MP, Bourdon JC | title = p53 Isoforms: An Intracellular Microprocessor? | journal = Genes & Cancer | volume = 2 | issue = 4 | pages = 453–65 | date = April 2011 | pmid = 21779513 | pmc = 3135639 | doi = 10.1177/1947601911408893 }}</ref><ref>{{cite journal | vauthors = Avery-Kiejda KA, Morten B, Wong-Brown MW, Mathe A, Scott RJ | title = The relative mRNA expression of p53 isoforms in breast cancer is associated with clinical features and outcome | journal = Carcinogenesis | volume = 35 | issue = 3 | pages = 586–96 | date = March 2014 | pmid = 24336193 | doi = 10.1093/carcin/bgt411 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Arsic N, Gadea G, Lagerqvist EL, Busson M, Cahuzac N, Brock C, Hollande F, Gire V, Pannequin J, Roux P | title = The p53 isoform Δ133p53β promotes cancer stem cell potential | journal = Stem Cell Reports | volume = 4 | issue = 4 | pages = 531–40 | date = April 2015 | pmid = 25754205 | pmc = 4400643 | doi = 10.1016/j.stemcr.2015.02.001 }}</ref> TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.<ref>{{cite journal | vauthors = Harami-Papp H, Pongor LS, Munkácsy G, Horváth G, Nagy ÁM, Ambrus A, Hauser P, Szabó A, Tretter L, Győrffy B | title = TP53 mutation hits energy metabolism and increases glycolysis in breast cancer | journal = Oncotarget | volume = 7 | issue = 41 | pages = 67183–67195 | date = October 2016 | pmid = 27582538 | pmc = 5341867 | doi = 10.18632/oncotarget.11594 }}</ref>

The dynamics of p53 proteins, along with its antagonist [[Mdm2]], indicate that the levels of p53, in units of concentration, [[oscillation|oscillate]] as a function of time. This "[[Damping ratio|damped]]" oscillation is both clinically documented <ref>{{cite journal | vauthors = Geva-Zatorsky N, Rosenfeld N, Itzkovitz S, Milo R, Sigal A, Dekel E, Yarnitzky T, Liron Y, Polak P, Lahav G, Alon U | title = Oscillations and variability in the p53 system | journal = Molecular Systems Biology | volume = 2 | pages = 2006.0033 | date = June 2006 | pmid = 16773083 | pmc = 1681500 | doi = 10.1038/msb4100068 }}</ref> and [[Mathematical modelling|mathematically modelled]].<ref>{{cite journal | vauthors = Proctor CJ, Gray DA | title = Explaining oscillations and variability in the p53-Mdm2 system | journal = BMC Systems Biology | volume = 2 | issue = 75 | pages = 75 | date = August 2008 | pmid = 18706112 | pmc = 2553322 | doi = 10.1186/1752-0509-2-75 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Chong KH, Samarasinghe S, Kulasiri D | title = Mathematical modelling of p53 basal dynamics and DNA damage response | journal = C-fACS | issue = 20th International Congress on Mathematical Modelling and Simulation | pages = 670–6 | date = December 2013| volume = 259 | doi = 10.1016/j.mbs.2014.10.010 | pmid = 25433195 }}</ref> Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as [[DNA repair|double-stranded breaks (DSB) or UV radiation]], are introduced to the [[Systems biology|system]]. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see [[#Regulation|p53 regulation]] for more information). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting ''de novo'' tissue-specific pharmacological [[drug discovery]]. {{cn|date=November 2024}}